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  • Phay M, Welzel AT, Williams AD, McWilliams-Koeppen HP, Blinder V, O'Malley TT, Solomon A, Walsh DM, O'Nuallain B. IgG Conformer's Binding to Amyloidogenic Aggregates. PLoS One. 2015 Sep 14;10(9):e0137344. doi: 10.1371/journal.pone.0137344. PubMed: 26367058. Categories: AmyloSENS

    IgG Conformer's Binding to Amyloidogenic Aggregates.

    PLoS One. 2015 Sep 14;10(9):e0137344. doi: 10.1371/journal.pone.0137344.

    IgG Conformer's Binding to Amyloidogenic Aggregates.

    Phay M, Welzel AT, Williams AD, McWilliams-Koeppen HP, Blinder V, O'Malley TT, Solomon A, Walsh DM, O'Nuallain B.

    Abstract

    Abstract:

    Amyloid-reactive IgGs isolated from pooled blood of normal individuals (pAbs) have demonstrated clinical utility for amyloid diseases by in vivo targeting and clearing amyloidogenic proteins and peptides. We now report the following three novel findings on pAb conformer's binding to amyloidogenic aggregates: 1) pAb aggregates have greater activity than monomers (HMW species > dimers > monomers), 2) pAbs interactions with amyloidogenic aggregates at least partially involves unconventional (non-CDR) interactions of F(ab) regions, and 3) pAb's activity can be easily modulated by trace aggregates generated during sample processing. Specifically, we show that HMW aggregates and dimeric pAbs present in commercial preparations of pAbs, intravenous immunoglobulin (IVIg), had up to ~200- and ~7-fold stronger binding to aggregates of Aβ and transthyretin (TTR) than the monomeric antibody. Notably, HMW aggregates were primarily responsible for the enhanced anti-amyloid activities of Aβ- and Cibacron blue-isolated IVIg IgGs. Human pAb conformer's binding to amyloidogenic aggregates was retained in normal human sera, and mimicked by murine pAbs isolated from normal pooled plasmas. An unconventional (non-CDR) component to pAb's activity was indicated from control human mAbs, generated against non-amyloid targets, binding to aggregated Aβ and TTR. Similar to pAbs, HMW and dimeric mAb conformers bound stronger than their monomeric forms to amyloidogenic aggregates. However, mAbs had lower maximum binding signals, indicating that pAbs were required to saturate a diverse collection of binding sites. Taken together, our findings strongly support further investigations on the physiological function and clinical utility of the inherent anti-amyloid activities of monomeric but not aggregated IgGs.

  • Planque SA, Nishiyama Y, Hara M, Sonoda S, Murphy SK, Watanabe K, Mitsuda Y, Brown EL, Massey RJ, Primmer SR, O'Nuallain B, Paul S. Physiological IgM class catalytic antibodies selective for transthyretin amyloid. J Biol Chem. 2014 May 9;289(19):13243-58. doi: 10.1074/jbc.M114.557231. PubMed: 24648510. Categories: AmyloSENS

    Physiological IgM class catalytic antibodies selective for transthyretin amyloid.

    J Biol Chem. 2014 May 9;289(19):13243-58. doi: 10.1074/jbc.M114.557231.

    Physiological IgM class catalytic antibodies selective for transthyretin amyloid.

    Planque SA, Nishiyama Y, Hara M, Sonoda S, Murphy SK, Watanabe K, Mitsuda Y, Brown EL, Massey RJ, Primmer SR, O'Nuallain B, Paul S.

    Abstract

    Abstract:

    Peptide bond-hydrolyzing catalytic antibodies (catabodies) could degrade toxic proteins, but acquired immunity principles have not provided evidence for beneficial catabodies. Transthyretin (TTR) forms misfolded β-sheet aggregates responsible for age-associated amyloidosis. We describe nucleophilic catabodies from healthy humans without amyloidosis that degraded misfolded TTR (misTTR) without reactivity to the physiological tetrameric TTR (phyTTR). IgM class B cell receptors specifically recognized the electrophilic analog of misTTR but not phyTTR. IgM but not IgG class antibodies hydrolyzed the particulate and soluble misTTR species. No misTTR-IgM binding was detected. The IgMs accounted for essentially all of the misTTR hydrolytic activity of unfractionated human serum. The IgMs did not degrade non-amyloidogenic, non-superantigenic proteins. Individual monoclonal IgMs (mIgMs) expressed variable misTTR hydrolytic rates and differing oligoreactivity directed to amyloid β peptide and microbial superantigen proteins. A subset of the mIgMs was monoreactive for misTTR. Excess misTTR was dissolved by a hydrolytic mIgM. The studies reveal a novel antibody property, the innate ability of IgMs to selectively degrade and dissolve toxic misTTR species as a first line immune function.

  • Phay M, Blinder V, Macy S, Greene MJ, Wooliver DC, Liu W, Planas A, Walsh DM, Connors LH, Primmer SR, Planque SA, Paul S, O'Nuallain B. Transthyretin aggregate-specific antibodies recognize cryptic epitopes on patient-derived amyloid fibrils. Rejuvenation Res. 2014 Apr;17(2):97-104. doi: 10.1089/rej.2013.1524. PubMed: 24164623. Categories: AmyloSENS

    Transthyretin aggregate-specific antibodies recognize cryptic epitopes on patient-derived amyloid fibrils.

    Rejuvenation Res. 2014 Apr;17(2):97-104. doi: 10.1089/rej.2013.1524.

    Transthyretin aggregate-specific antibodies recognize cryptic epitopes on patient-derived amyloid fibrils.

    Phay M, Blinder V, Macy S, Greene MJ, Wooliver DC, Liu W, Planas A, Walsh DM, Connors LH, Primmer SR, Planque SA, Paul S, O'Nuallain B.

    Abstract

    Abstract:

    Amyloidosis involves the extracellular deposition of proteinaceous amyloid fibrils and accessory molecules in organ(s) and/or tissue(s), and is associated with a host of human diseases, including Alzheimer disease, diabetes, and heart disease. Unfortunately, the amyloidoses are currently incurable, and there is an urgent need for less invasive diagnostics. To address this, we have generated 22 monoclonal antibodies (mAbs) against aggregates formed by a blood transport protein, transthyretin (TTR), which primarily forms amyloid fibrils in a patient's heart and/or peripheral nerves. Four of the mAbs, 2T5C9, 2G9C, T1F11, and TB2H7, demonstrated diagnostic potential in enzyme-linked immunosorbent assays (ELISA) by their low to sub-nanomolar cross-reactivity with recombinant wild-type (WT) and mutant TTR aggregates and lack of binding to native TTR or amyloid fibrils formed by other peptides or proteins. Notably, in the presence of normal human sera, three of the four mAbs, 2T5C9, 2G9C, and T1F11, retained low nM binding to TTR amyloid fibrils derived from two patients with familial amyloidotic polyneuropathy (FAP). The two most promising mAbs, 2T5C9 and 2G9C, were also shown by immunohistochemistry to have low nM binding to TTR amyloid deposits in cardiac tissue sections from two FAP patients. Taken together, these findings strongly support further investigations on the diagnostic utility of TTR aggregate specific mAbs for patients with TTR amyloidoses.

  • Peto MV. Aluminium and iron in humans: bioaccumulation, pathology, and removal. Rejuvenation Res 2010 Oct;13(5):589-98. PubMed: 21142669. Categories: AmyloSENS, LysoSENS, OncoSENS

    Aluminium and iron in humans: bioaccumulation, pathology, and removal.

    Rejuvenation Res 2010 Oct;13(5):589-98.

    Aluminium and iron in humans: bioaccumulation, pathology, and removal.

    Peto MV.

    Abstract

    Abstract:

    It is well known that exposure to various elements has a noticeable effect on human health. The effect of an element is determined by several characteristics, including its similarity to elements of biological necessity, metabolism, and degree of interaction with physiological processes. This review investigates the scientific literature of iron and aluminium to evaluate the extent to which these elements accumulate and cause pathology in humans. Iron was chosen for review because it is necessary for human life while seemingly having relationships with numerous pathological states such as heart disease, cancer, and impaired insulin sensitivity. Aluminium is reviewed because of its prevalence in daily life, observed interference with several biological processes, controversial relationship with Alzheimer disease, and lack of physiological role. Furthermore, because each of these metals has long been investigated for a possible relationship with various pathological states, a substantial volume of research is available regarding the effects of iron and aluminium in biological systems. For both aluminium and iron, this review focuses on: (1) Evaluating the evidence of toxicity, (2) considering the possibility of bioaccumulation, and (3) exploring methods of managing their accumulation.

  • Balakrishnan K, Andrei-Selmer LC, Selmer T, Bacher M, Dodel R. Comparison of Intravenous Immunoglobulins for Naturally Occurring Autoantibodies against Amyloid-beta. J Alzheimers Dis. 2010 Feb 17. [Epub ahead of print] PubMed: 20164596. Categories: AmyloSENS

    Comparison of Intravenous Immunoglobulins for Naturally Occurring Autoantibodies against Amyloid-beta.

    J Alzheimers Dis. 2010 Feb 17. [Epub ahead of print]

    Comparison of Intravenous Immunoglobulins for Naturally Occurring Autoantibodies against Amyloid-beta.

    Balakrishnan K, Andrei-Selmer LC, Selmer T, Bacher M, Dodel R.

    Abstract

    Abstract:

    Intravenous immunoglobulins (IVIG) are currently used for therapeutic purposes in autoimmune disorders. Recently, we demonstrated the presence of naturally occurring antibodies against amyloid-beta (nAbs-Abeta) within the pool of IVIG. In this study, we compared different brands of IVIG for nAbs-Abeta and have found differences in the specificity of the nAbs-Abeta towards Abeta_{1-40} and Abeta_{1-42}. We analyzed the influence of a pH-shift over the course of antibody storage using ELISA and investigated antibody dimerization at acidic and neutral pH as well as differences in the IgG subclass distributions among the IVIG using both HPLC and a nephelometric assay. Furthermore, we investigated the epitope region of purified nAbs-Abeta. The differences found in Abeta specificity are not directly proportionate to the binding nature of these antibodies when administered in vivo. This information, however, may serve as a guide when choosing the commercial source of IVIG for therapeutic applications in Alzheimer's disease.

  • Vellas B, Black R, Thal LJ, Fox NC, Daniels M, McLennan G, Tompkins C, Leibman C, Pomfret M, Grundman M; AN1792 (QS-21)-251 Study Team. Long-term follow-up of patients immunized with AN1792: reduced functional decline in antibody responders. Curr Alzheimer Res 2009;6(2):144-51. PubMed: 19355849. Categories: AmyloSENS

    Long-term follow-up of patients immunized with AN1792: reduced functional decline in antibody responders.

    Curr Alzheimer Res 2009;6(2):144-51.

    Long-term follow-up of patients immunized with AN1792: reduced functional decline in antibody responders.

    Vellas B, Black R, Thal LJ, Fox NC, Daniels M, McLennan G, Tompkins C, Leibman C, Pomfret M, Grundman M; AN1792 (QS-21)-251 Study Team.

    Abstract

    Abstract:

    BACKGROUND: Immunization of patients with Alzheimer's disease (AD) with synthetic amyloid-beta peptide (Abeta(42)) (AN1792) was previously studied in a randomized, double-blind, placebo-controlled phase 2a clinical trial, Study AN1792(QS-21)-201. Treatment was discontinued following reports of encephalitis. One year follow-up revealed that AN1792 antibody responders showed improvements in cognitive measures as assessed by the neuropsychological test battery (NTB) and a decrease in brain volume compared with placebo. METHODS: A follow-up study, Study AN1792(QS-21)-251, was conducted to assess the long-term functional, psychometric, neuroimaging, and safety outcomes of patients from the phase 2a study 4.6 years after immunization with AN1792. The results were analyzed by comparing patients originally identified as antibody responders in the AN1792 phase 2a study with placebo-treated patients. RESULTS: One hundred and fifty-nine patients/caregivers (30 placebo; 129 AN1792) participated in this follow-up study. Of the 129 AN1792-treated patients, 25 were classified in the phase 2a study as antibody responders (anti-AN1792 titers > or = 1:2,200 at any time after the first injection). Low but detectable, sustained anti-AN1792 titers were found in 17 of 19 samples obtained from patients classified as antibody responders in the phase 2a study. No detectable anti-AN1792 antibodies were found in patients not classified as antibody responders in the phase 2a study. Significantly less decline was observed on the Disability Assessment for Dementia scale among antibody responders than placebo-treated patients (p=0.015) after 4.6 years. Significant differences in favor of responders were also observed on the Dependence Scale (p=0.033). Of the small number of patients who underwent a follow-up MRI, antibody responders showed similar brain volume loss during the follow-up period subsequent to the AN1792 phase 2a study compared with placebo-treated patients. CONCLUSIONS: Approximately 4.6 years after immunization with AN1792, patients defined as responders in the phase 2a study maintained low but detectable, sustained anti-AN1792 antibody titers and demonstrated significantly reduced functional decline compared with placebo-treated patients. Brain volume loss in antibody responders was not significantly different from placebo-treated patients approximately 3.6 years from the end of the original study. No further cases of encephalitis were noted. These data support the hypothesis that Abeta immunotherapy may have long-term functional benefits.

  • Pride M, Seubert P, Grundman M, Hagen M, Eldridge J, Black RS. Progress in the active immunotherapeutic approach to Alzheimer's disease: clinical investigations into AN1792-associated meningoencephalitis. Neurodegener Dis 2008;5(3-4):194-196. PubMed: 18322388. Categories: AmyloSENS

    Progress in the active immunotherapeutic approach to Alzheimer's disease: clinical investigations into AN1792-associated meningoencephalitis.

    Neurodegener Dis 2008;5(3-4):194-196.

    Progress in the active immunotherapeutic approach to Alzheimer's disease: clinical investigations into AN1792-associated meningoencephalitis.

    Pride M, Seubert P, Grundman M, Hagen M, Eldridge J, Black RS.

    Abstract

    Abstract:

    BACKGROUND: In a phase 2a clinical trial of AN1792 (Study 201), a potential immunotherapeutic agent for use in Alzheimer's disease (AD), approximately 6% of the treated AD patients (18/300) developed meningoencephalitis (ME). OBJECTIVE: To elucidate potential immune mechanisms of treatment-induced ME. METHODS: Peripheral blood mononuclear cells obtained from patients who received AN1792 were stimulated in vitro either with beta-amyloid (Abeta) or various overlapping peptides of Abeta(1-42), followed by quantification of cytokine-secreting cells by enzyme-linked immunosorbent spot assay. RESULTS: A significant difference in the quality of the T-cell responses between patients in Study 201 and those in earlier studies of AN1792 was noted. T-cell responses specific to the carboxy terminus of Abeta elicited from patients' peripheral blood mononuclear cells in an earlier multiple dose study (Study 102) were Th2 biased, while those from Study 201 were biased toward a proinflammatory Th1 response. Antibody responses in both studies were quantitatively and qualitatively similar (as determined by epitope mapping). The addition of polysorbate 80 to the formulation used in Study 201 is the most likely explanation for the difference in the T-cell response. CONCLUSION: ME following injection of AN1792 may be related to immune response differences driven by a formulation change. To address this, a novel peptide-carrier protein conjugate using an amino-terminal fragment of Abeta (ACC-001) has been developed to avoid potentially harmful T-cell responses, while maintaining a similar antibody response to that of AN1792. Immunotherapeutic trials using this treatment approach in AD patients are in progress.

  • Bombois S, Maurage CA, Gompel M, Deramecourt V, Mackowiak-Cordoliani MA, Black RS, Lavielle R, Delacourte A, Pasquier F. Absence of beta-amyloid deposits after immunization in Alzheimer disease with Lewy body dementia. Arch Neurol 2007;64(4):583-587. PubMed: 17420322. Categories: AmyloSENS

    Absence of beta-amyloid deposits after immunization in Alzheimer disease with Lewy body dementia.

    Arch Neurol 2007;64(4):583-587.

    Absence of beta-amyloid deposits after immunization in Alzheimer disease with Lewy body dementia.

    Bombois S, Maurage CA, Gompel M, Deramecourt V, Mackowiak-Cordoliani MA, Black RS, Lavielle R, Delacourte A, Pasquier F.

    Abstract

    Abstract:

    OBJECTIVE: To describe the neuropathological and biochemical findings of the brain examination of a patient enrolled in the AN-1792(QS-21) trial with an initial clinical diagnosis of Alzheimer disease (AD), in whom Lewy body variant was thereafter clinically diagnosed. DESIGN: A case report. SETTING: University memory clinic. Patient A 74-year-old woman with clinical features of probable AD. Intervention The patient received 2 injections of 225 mug of AN-1792 (beta-amyloid [Abeta]) plus 50 mug of the adjuvant QS-21 at an interval of 4 weeks. The patient was an antibody responder with an IgG anti-AN-1792 antibody titer exceeding 10 000 and an IgM titer exceeding 3500. Maximum serum anti-Abeta titers were reached in 4.7 months. During the 3 following years, while the Mini-Mental State Examination score remained globally stable despite several confusional episodes, she developed clinical features of dementia with Lewy bodies. The patient died 34 months postimmunization. An autopsy was performed. MAIN OUTCOME MEASURES: Neuropathological and biochemical examination of the brain using standardized evaluation for tau, beta-amyloid, and synuclein deposits. RESULTS: Neither neuropathological nor biochemical examinations showed amyloid deposit in the brain of this immunized patient. For tau deposition, Braak stage was IV/VI, and the Western blot analysis score was 9c/10. The neuropathological semiquantitative score for alpha-synuclein aggregation was 4. There was no inflammation. These results were compared with those of an age-matched patient with AD and a control devoid of any neurological disease. CONCLUSION: In this Lewy body variant case, with globally stable functional and cognitive features, Abeta immunization resulted in a significant clearance of amyloid deposits, with remaining tau and synuclein pathological features in the brain. Patients with a Lewy body variant of AD should not be excluded from enrollment in Abeta-immunization trials.

  • Qu B, Boyer PJ, Johnston SA, Hynan LS, Rosenberg RN. Abeta42 gene vaccination reduces brain amyloid plaque burden in transgenic mice. J Neurol Sci 2006;244(1-2):151-8. PubMed: 16556449. Categories: AmyloSENS

    Abeta42 gene vaccination reduces brain amyloid plaque burden in transgenic mice.

    J Neurol Sci 2006;244(1-2):151-8.

    Abeta42 gene vaccination reduces brain amyloid plaque burden in transgenic mice.

    Qu B, Boyer PJ, Johnston SA, Hynan LS, Rosenberg RN.

    Abstract

    Abstract:

    OBJECTIVE: To demonstrate that in APPswe/PS1DeltaE9 transgenic mice, gene gun mediated Abeta42 gene vaccination elicits a high titer of anti-Abeta42 antibodies causal of a significant reduction of Abeta42 deposition in brain. METHODS: Gene gun immunization is conducted with transgenic mice using the Abeta42 gene in a bacterial plasmid with the pSP72-E3L-Abeta42 construct. Enzyme-linked immunoabsorbent assays (ELISA) and Western blots are used to monitor anti-Abeta42 antibody levels in serum and Abeta42 levels in brain tissues. Enzyme-linked immunospot (ELISPOT) assays are used for detection of peripheral blood T cells to release gamma-interferon. Immunofluorescence detection of Abeta42 plaques and quantification of amyloid burden of brain tissue were measured and sections were analyzed with Image J (NIH) software. RESULTS: Gene gun vaccination with the Abeta42 gene resulted in high titers of anti-Abeta42 antibody production of the Th2-type. Levels of Abeta42 in treated transgenic mouse brain were reduced by 60-77.5%. The Mann-Whitney U-test P=0.0286. INTERPRETATION: We have developed a gene gun mediated Abeta42 gene vaccination method that is efficient to break host Abeta42 tolerance without using adjuvant and induces a Th2 immune response. Abeta42 gene vaccination significantly reduces the Abeta42 burden of the brain in treated APPswe/PS1DeltaE9 transgenic mice with no overlap between treated and control mice.

  • Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ. A 24-week open-label extension study of memantine in moderate to severe Alzheimer disease. Arch Neurol 2006;63(1):49-54. PubMed: 16401736. Categories: AmyloSENS

    A 24-week open-label extension study of memantine in moderate to severe Alzheimer disease.

    Arch Neurol 2006;63(1):49-54.

    A 24-week open-label extension study of memantine in moderate to severe Alzheimer disease.

    Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ.

    Abstract

    Abstract:

    BACKGROUND: This study is an extension of a 28-week, randomized, double-blind, placebo-controlled study of memantine in 252 patients with moderate to severe Alzheimer disease. OBJECTIVE: To evaluate long-term memantine treatment in moderate to severe Alzheimer disease. DESIGN, SETTING, AND PATIENTS: Open-label, 24-week extension trial. Raters remained blind to the patients' initial study treatment. Patients (n = 175) were enrolled from the previous double-blind study in an outpatient setting. INTERVENTION: Twenty mg of memantine was given daily. MAIN OUTCOME MEASURES: Efficacy assessments from the double-blind study were continued and safety parameters were monitored. RESULTS: Patients who switched to memantine treatment from their previous placebo therapy experienced a significant benefit in all main efficacy assessments (functional, global, and cognitive) relative to their mean rate of decline with placebo treatment during the double-blind period (P<.05). The completion rate for the extension phase of the study was high (78%) and the favorable adverse event profile for memantine therapy was similar to that seen in the double-blind study. CONCLUSION: These results extend previous findings that demonstrated the efficacy and safety of memantine in the treatment of patients with moderate to severe Alzheimer disease.

  • Masliah E, Hansen L, Adame A, Crews L, Bard F, Lee C, Seubert P, Games D, Kirby L, Schenk D. Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology 2005;64(1):129-131. PubMed: 15642916. Categories: AmyloSENS

    Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease.

    Neurology 2005;64(1):129-131.

    Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease.

    Masliah E, Hansen L, Adame A, Crews L, Bard F, Lee C, Seubert P, Games D, Kirby L, Schenk D.

    Abstract

    Abstract:

    The authors report a patient with Alzheimer disease (AD) without encephalitis who was immunized with AN-1792 (an adjuvanted formulation of Abeta-42). There were no amyloid plaques in the frontal cortex and abundant Abeta-immunoreactive macrophages, but tangles and amyloid angiopathy were present. The white matter appeared normal and minimal lymphocytic infiltration in the leptomeninges was observed. This case illustrates the effects of an Abeta-based immunization on AD pathogenesis in the absence of overt meningoencephalitis and leukoencephalopathy.

  • Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, Cuervo AM. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 2005;64(2):113-122. PubMed: 15751225. Categories: AmyloSENS, LysoSENS

    Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study.

    J Neuropathol Exp Neurol 2005;64(2):113-122.

    Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study.

    Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, Cuervo AM.

    Abstract

    Abstract:

    The accumulation of lysosomes and their hydrolases within neurons is a well-established neuropathologic feature of Alzheimer disease (AD). Here we show that lysosomal pathology in AD brain involves extensive alterations of macroautophagy, an inducible pathway for the turnover of intracellular constituents, including organelles. Using immunogold labeling with compartmental markers and electron microscopy on neocortical biopsies from AD brain, we unequivocally identified autophagosomes and other prelysosomal autophagic vacuoles (AVs), which were morphologically and biochemically similar to AVs highly purified from mouse liver. AVs were uncommon in brains devoid of AD pathology but were abundant in AD brains particularly, within neuritic processes, including synaptic terminals. In dystrophic neurites, autophagosomes, multivesicular bodies, multilamellar bodies, and cathepsin-containing autophagolysosomes were the predominant organelles and accumulated in large numbers. These compartments were distinguishable from lysosomes and lysosomal dense bodies, previously shown also to be abundant in dystrophic neurites. Autophagy was evident in the perikarya of affected neurons, particularly in those with neurofibrillary pathology where it was associated with a relative depletion of mitochondria and other organelles. These observations provide the first evidence that macroautophagy is extensively involved in the neurodegenerative/regenerative process in AD. The striking accumulations of immature AV forms in dystrophic neurites suggest that the transport of AVs and their maturation to lysosomes may be impaired, thereby impeding the suspected neuroprotective functions of autophagy.

  • Gilman S, Koller M, Black RS, Griffith SG, Fox NC, Eisner L, Kirby L, Rovira MB, Forette F, Orgogozo JM; AN1792(QS-21)-201 Study Team. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 2005;64(9):1553-1562. PubMed: 15883316. Categories: AmyloSENS

    Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial.

    Neurology 2005;64(9):1553-1562.

    Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial.

    Gilman S, Koller M, Black RS, Griffith SG, Fox NC, Eisner L, Kirby L, Rovira MB, Forette F, Orgogozo JM; AN1792(QS-21)-201 Study Team.

    Abstract

    Abstract:

    BACKGROUND: AN1792 (beta-amyloid [Abeta]1-42) immunization reduces Abeta plaque burden and preserves cognitive function in APP transgenic mice. The authors report the results of a phase IIa immunotherapy trial of AN1792(QS-21) in patients with mild to moderate Alzheimer disease (AD) that was interrupted because of meningoencephalitis in 6% of immunized patients. METHODS: This randomized, multicenter, placebo-controlled, double-blind trial of IM AN1792 225 microg plus the adjuvant QS-21 50 microg (300 patients) and saline (72 patients) included patients aged 50 to 85 years with probable AD, Mini-Mental State Examination (MMSE) 15 to 26. Injections were planned for months 0, 1, 3, 6, 9, and 12. Safety and tolerability were evaluated, and pilot efficacy (AD Assessment Scale-Cognitive Subscale [ADAS-Cog], MRI, neuropsychological test battery [NTB], CSF tau, and Abeta42) was assessed in anti-AN1792 antibody responder patients (immunoglobulin G titer > or = 1:2,200). RESULTS: Following reports of meningoencephalitis (overall 18/300 [6%]), immunization was stopped after one (2 patients), two (274 patients), or three (24 patients) injections. Of the 300 AN1792(QS-21)-treated patients, 59 (19.7%) developed the predetermined antibody response. Double-blind assessments were maintained for 12 months. No significant differences were found between antibody responder and placebo groups for ADAS-Cog, Disability Assessment for Dementia, Clinical Dementia Rating, MMSE, or Clinical Global Impression of Change, but analyses of the z-score composite across the NTB revealed differences favoring antibody responders (0.03 +/- 0.37 vs -0.20 +/- 0.45; p = 0.020). In the small subset of subjects who had CSF examinations, CSF tau was decreased in antibody responders (n = 11) vs placebo subjects (n = 10; p < 0.001). CONCLUSION: Although interrupted, this trial provides an indication that Abeta immunotherapy may be useful in Alzheimer disease.

  • Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM. Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron 2005;45(5):675-688. PubMed: 15748844. Categories: AmyloSENS

    Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice.

    Neuron 2005;45(5):675-688.

    Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice.

    Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM.

    Abstract

    Abstract:

    Progressive memory loss and cognitive dysfunction are the hallmark clinical features of Alzheimer's disease (AD). Identifying the molecular triggers for the onset of AD-related cognitive decline presently requires the use of suitable animal models, such as the 3xTg-AD mice, which develop both amyloid and tangle pathology. Here, we characterize the onset of learning and memory deficits in this model. We report that 2-month-old, prepathologic mice are cognitively unimpaired. The earliest cognitive impairment manifests at 4 months as a deficit in long-term retention and correlates with the accumulation of intraneuronal Abeta in the hippocampus and amygdala. Plaque or tangle pathology is not apparent at this age, suggesting that they contribute to cognitive dysfunction at later time points. Clearance of the intraneuronal Abeta pathology by immunotherapy rescues the early cognitive deficits on a hippocampal-dependent task. Reemergence of the Abeta pathology again leads to cognitive deficits. This study strongly implicates intraneuronal Abeta in the onset of cognitive dysfunction.

  • Ferrer I, Boada Rovira M, Sánchez Guerra ML, Rey MJ, Costa-Jussá F. Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer's disease. Brain Pathol 2004;14(1):11-20. PubMed: 14997933. Categories: AmyloSENS

    Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer's disease.

    Brain Pathol 2004;14(1):11-20.

    Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer's disease.

    Ferrer I, Boada Rovira M, Sánchez Guerra ML, Rey MJ, Costa-Jussá F.

    Abstract

    Abstract:

    Immunizing transgenic PDAPP mice, which overexpress mutant APP and develop beta-amyloid deposition resembling plaques in Alzheimer's disease (AD), results in a decrease of amyloid burden when compared with non-treated transgenic animals. Immunization with amyloid-beta peptide has been initiated in a randomised pilot study in AD. Yet a minority of patients developed a neurological complication consistent with meningoencephalitis and one patient died; the trial has been stopped. Neuropathological examination in that patient showed meningoencephalitis, and focal atypically low numbers of diffuse and neuritic plaques but not of vascular amyloid, nor regression of tau pathology in neurofibrillary tangles and neuropil threads. The present neuropathological study reports the second case of meningoencephalitis following immunization with amyloid-beta peptide in AD, and has been directed toward exploring mechanisms underlying decreased tau pathology in relation with amyloid deposit regression, and possible molecular bases involved in the inflammatory response following immunization. Inflammatory infiltrates were composed of CD8+, CD4+, CD3+, CD5+ and, rarely, CD7+ lymphocytes, whereas B lymphocytes and T cytotoxic cells CD16, CD57, TIA and graenzyme were negative. Characteristic neuropathological findings were focal depletion of diffuse and neuritic plaques, but not of amyloid angiopathy, and the presence of small numbers of extremely dense (collapsed) plaques surrounded by active microglia, and multinucleated giant cells filled with dense Abeta42 and Abeta40, in addition to severe small cerebral blood vessel disease and multiple cortical hemorrhages. Reduced amyloid burden was accompanied by low amyloid-associated oxidative stress responses (reduced superoxide dismutase-1: SOD-1 expression) and by local inhibition of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 kinase which are involved in tau phosphorylation. These results support the amyloid cascade of tau phosphorylation in AD regarding phosphorylation of tau dependent on beta-amyloid deposition in neuritic plaques, but not of tau in neurofibrillary tangles and threads. Furthermore, amyloid reduction was accompanied by increased expression of the PA28a/beta inductor, and of LMP7, LMP2 and MECL1 subunits of the immunoproteasome in microglial and inflammatory cells surrounding collapsed plaques, and in multinucleated giant cells. Immunoproteasome subunit expression was accompanied by local presentation of MHC class I molecules. Release of antigenic peptides derived from beta-amyloid processing may enhance T-cell inflammatory responses accounting for the meningoencephalitis following amyloid-beta peptide immunization.

  • Lemere CA, Beierschmitt A, Iglesias M, Spooner ET, Bloom JK, Leverone JF, Zheng JB, Seabrook TJ, Louard D, Li D, Selkoe DJ, Palmour RM, Ervin FR. Alzheimer's disease abeta vaccine reduces central nervous system abeta levels in a non-human primate, the Caribbean vervet. Am J Pathol 2004;165(1):283-297. PubMed: 15215183. Categories: AmyloSENS

    Alzheimer's disease abeta vaccine reduces central nervous system abeta levels in a non-human primate, the Caribbean vervet.

    Am J Pathol 2004;165(1):283-297.

    Alzheimer's disease abeta vaccine reduces central nervous system abeta levels in a non-human primate, the Caribbean vervet.

    Lemere CA, Beierschmitt A, Iglesias M, Spooner ET, Bloom JK, Leverone JF, Zheng JB, Seabrook TJ, Louard D, Li D, Selkoe DJ, Palmour RM, Ervin FR.

    Abstract

    Abstract:

    Amyloid beta (Abeta) protein immunotherapy lowers cerebral Abeta and improves cognition in mouse models of Alzheimer's disease (AD). Here we show that Caribbean vervet monkeys (Chlorocebus aethiops, SK) develop cerebral Abeta plaques with aging and that these deposits are associated with gliosis and neuritic dystrophy. Five aged vervets were immunized with Abeta peptide over 10 months. Plasma and cerebral spinal fluid (CSF) samples were collected periodically from the immunized vervets and five aged controls; one monkey per group expired during the study. By Day 42, immunized animals generated plasma Abeta antibodies that labeled Abeta plaques in human, AD transgenic mouse and vervet brains; bound Abeta1-7; and recognized monomeric and oligomeric Abeta but not full-length amyloid precursor protein nor its C-terminal fragments. Low anti-Abeta titers were detected in CSF. Abetax-40 levels were elevated approximately 2- to 5-fold in plasma and decreased up to 64% in CSF in immunized vervets. Insoluble Abetax-42 was decreased by 66% in brain homogenates of the four immunized animals compared to archival tissues from 13 age-matched control vervets. Abeta42-immunoreactive plaques were detected in frontal cortex in 11 of the 13 control animals, but not in six brain regions examined in each of the four immunized vervets. No T cell response or inflammation was observed. Our study is the first to demonstrate age-related Abeta deposition in the vervet monkey as well as the lowering of cerebral Abeta by Abeta vaccination in a non-human primate. The findings further support Abeta immunotherapy as a potential prevention and treatment of AD.

  • Courtney C, Farrell D, Gray R, Hills R, Lynch L, Sellwood E, Edwards S, Hardyman W, Raftery J, Crome P, Lendon C, Shaw H, Bentham P; AD2000 Collaborative Group. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomized double-blind trial. Lancet 2004;363(9427):2105-2115. PubMed: 15220031. Categories: AmyloSENS

    Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomized double-blind trial.

    Lancet 2004;363(9427):2105-2115.

    Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomized double-blind trial.

    Courtney C, Farrell D, Gray R, Hills R, Lynch L, Sellwood E, Edwards S, Hardyman W, Raftery J, Crome P, Lendon C, Shaw H, Bentham P; AD2000 Collaborative Group.

    Abstract

    Abstract:

    BACKGROUND: Cholinesterase inhibitors produce small improvements in cognitive and global assessments in Alzheimer's disease. We aimed to determine whether donepezil produces worthwhile improvements in disability, dependency, behavioural and psychological symptoms, carers' psychological wellbeing, or delay in institutionalisation. If so, which patients benefit, from what dose, and for how long? METHODS: 565 community-resident patients with mild to moderate Alzheimer's disease entered a 12-week run-in period in which they were randomly allocated donepezil (5 mg/day) or placebo. 486 who completed this period were rerandomised to either donepezil (5 or 10 mg/day) or placebo, with double-blind treatment continuing as long as judged appropriate. Primary endpoints were entry to institutional care and progression of disability, defined by loss of either two of four basic, or six of 11 instrumental, activities on the Bristol activities of daily living scale (BADLS). Outcome assessments were sought for all patients and analysed by logrank and multilevel models. FINDINGS: Cognition averaged 0.8 MMSE (mini-mental state examination) points better (95% CI 0.5-1.2; p<0.0001) and functionality 1.0 BADLS points better (0.5-1.6; p<0.0001) with donepezil over the first 2 years. No significant benefits were seen with donepezil compared with placebo in institutionalisation (42% vs 44% at 3 years; p=0.4) or progression of disability (58% vs 59% at 3 years; p=0.4). The relative risk of entering institutional care in the donepezil group compared with placebo was 0.97 (95% CI 0.72-1.30; p=0.8); the relative risk of progression of disability or entering institutional care was 0.96 (95% CI 0.74-1.24; p=0.7). Similarly, no significant differences were seen between donepezil and placebo in behavioural and psychological symptoms, carer psychopathology, formal care costs, unpaid caregiver time, adverse events or deaths, or between 5 mg and 10 mg donepezil. INTERPRETATION: Donepezil is not cost effective, with benefits below minimally relevant thresholds. More effective treatments than cholinesterase inhibitors are needed for Alzheimer's disease.

  • Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC, Jouanny P, Dubois B, Eisner L, Flitman S, Michel BF, Boada M, Frank A, Hock C. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 2003;61(1):46-54. PubMed: 12847155. Categories: AmyloSENS

    Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization.

    Neurology 2003;61(1):46-54.

    Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization.

    Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC, Jouanny P, Dubois B, Eisner L, Flitman S, Michel BF, Boada M, Frank A, Hock C.

    Abstract

    Abstract:

    BACKGROUND: AD is characterized by cerebral deposition of beta-amyloid plaques with amyloid beta-peptide (Abeta) 42 as the major peptide constituent, along with neurofibrillary tangles and neuronal loss. In transgenic mice, active immunization against Abeta42 removes these plaques and improves cognitive function. A Phase I study in AD patients demonstrated good safety and tolerability of multiple injections of aggregated Abeta42 (AN1792) with QS-21 as adjuvant. METHODS: Three hundred seventy-two patients with mild to moderate AD were randomized to receive IM injections of AN1792 or placebo (4:1) at baseline and at months 1, 3, 6, 9, and 12 in a multicenter Phase II safety, tolerability, and pilot efficacy study. Dosing was terminated after four early reports of meningoencephalitis, but follow-up continued. The study remains blinded, and further results will be reported after its termination. RESULTS: Symptoms and laboratory findings consistent with meningoencephalitis occurred in 18 of 298 (6%) patients treated with AN1792 compared with 0 of 74 on placebo (p = 0.020). Sixteen of the 18 had received two doses, one had received one dose, and one had received three doses of the study drug before symptoms occurred. The median latency from the first and last injections to symptoms was 75 and 40 days. No case occurred later than 6 months after the first immunization. Anti-Abeta42 antibody titers were not correlated with the occurrence or severity of symptoms or relapses. Twelve patients recovered to or close to baseline within weeks, whereas six remain with disabling cognitive or neurologic sequelae. All 18 patients remain alive to date (December 31, 2002), 6 months to >1 year after symptom onset. CONCLUSIONS: Postvaccination meningoencephalitis occurred without clear relation to serum anti-Abeta42 antibody titers. Potential mechanisms such as T-cell and microglial activation may be responsible and are under consideration to develop a safer anti-Abeta immunotherapy for AD.

  • Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 2003;9(4):448-452. PubMed: 12640446. Categories: AmyloSENS

    Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report.

    Nat Med 2003;9(4):448-452.

    Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report.

    Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO.

    Abstract

    Abstract:

    Amyloid-beta peptide (Abeta) has a key role in the pathogenesis of Alzheimer disease (AD). Immunization with Abeta in a transgenic mouse model of AD reduces both age-related accumulation of Abeta in the brain and associated cognitive impairment. Here we present the first analysis of human neuropathology after immunization with Abeta (AN-1792). Comparison with unimmunized cases of AD (n = 7) revealed the following unusual features in the immunized case, despite diagnostic neuropathological features of AD: (i) there were extensive areas of neocortex with very few Abeta plaques; (ii) those areas of cortex that were devoid of Abeta plaques contained densities of tangles, neuropil threads and cerebral amyloid angiopathy (CAA) similar to unimmunized AD, but lacked plaque-associated dystrophic neurites and astrocyte clusters; (iii) in some regions devoid of plaques, Abeta-immunoreactivity was associated with microglia; (iv) T-lymphocyte meningoencephalitis was present; and (v) cerebral white matter showed infiltration by macrophages. Findings (i)-(iii) strongly resemble the changes seen after Abeta immunotherapy in mouse models of AD and suggest that the immune response generated against the peptide elicited clearance of Abeta plaques in this patient. The T-lymphocyte meningoencephalitis is likely to correspond to the side effect seen in some other patients who received AN-1792 (refs. 7-9).

  • Solomon A, Weiss DT, Wall JS. Immunotherapy in systemic primary (AL) amyloidosis using amyloid-reactive monoclonal antibodies. Cancer Biother Radiopharm 2003;18(6):853-860. PubMed: 14969598. Categories: AmyloSENS

    Immunotherapy in systemic primary (AL) amyloidosis using amyloid-reactive monoclonal antibodies.

    Cancer Biother Radiopharm 2003;18(6):853-860.

    Immunotherapy in systemic primary (AL) amyloidosis using amyloid-reactive monoclonal antibodies.

    Solomon A, Weiss DT, Wall JS.

    Abstract

    Abstract:

    Heretofore, treatment of patients with primary or light chain-associated (AL) amyloidosis has been directed toward reducing the synthesis of the amyloidogenic precursor protein through conventional or high-dose cytotoxic antiplasma cell chemotherapy. Although such efforts have extended survival, most often the prognosis remains exceedingly poor due to the persistence (or progression) of the pathologic deposits. The development of murine amyloid-reactive monoclonal antibodies (mAbs) has provided another therapeutic approach; namely, passive immunotherapy. These reagents, prepared against human light chain-related fibrils, recognize an epitope common to the beta-pleated structure of AL and other types of amyloid proteins and can effect rapid amyloidolysis when administered to mice injected with human AL amyloid extracts. One such prototypic antibody, the IgG1kappa mAb 11-1F4, has now been chimerized and is undergoing GMP production for an eventual phase I and II clinical trial in patients with AL amyloidosis. Demonstration of the therapeutic efficacy of this amyloid-reactive mAb would provide an important proof-of-principle that this form of immunotherapy also could benefit individuals with other types of inherited or acquired amyloid-associated disease.

  • Solomon A, Weiss DT, Wall JS. Therapeutic potential of chimeric amyloid-reactive monoclonal antibody 11-1F4. Clin Cancer Res 2003;9(10 Pt 2):3831S-3838S. PubMed: 14506180. Categories: AmyloSENS

    Therapeutic potential of chimeric amyloid-reactive monoclonal antibody 11-1F4.

    Clin Cancer Res 2003;9(10 Pt 2):3831S-3838S.

    Therapeutic potential of chimeric amyloid-reactive monoclonal antibody 11-1F4.

    Solomon A, Weiss DT, Wall JS.

    Abstract

    Abstract:

    PURPOSE: We had previously reported that certain of our murine (m) antihuman light chain monoclonal antibodies (mAbs) recognized an epitope common to AL and other types of amyloid fibrils. On the basis of this evidence, one such antibody, 11-1F4, was administered to mice bearing AL amyloidomas induced by s.c. injection of human AL extracts. The mAb bound to the amyloid and initiated an Fc-mediated cellular inflammatory response that led to rapid reduction in the tumor masses. To develop this reagent for clinical use, the 11-1F4 mAb was chimerized and its activity compared with that of the unmodified antibody. EXPERIMENTAL DESIGN: The chimeric (c) 11-1F4 mAb was produced in CHOdhfr-stable mammalian cell lines that had been transfected with a supervector DNA encoding the mouse 11-1F4 heavy and light chain variable regions (V(H), V(L)) and human heavy and light chain constant regions (C(H), C(L)). The antibody products were analyzed for their fibril binding activity and ability to effect amyloidolysis in two in vivo experimental models. RESULTS: The capability of the c11-1F4 mAb to interact with amyloid was demonstrated in vitro. Administration of this reagent into mice bearing human AL tumors or those with systemic AA deposits resulted in marked reduction in amyloid burden with no evidence of toxicity in the animals. CONCLUSIONS: These results have led to the decision to produce GMP-grade c11-1F4 for a Phase I/II clinical trial in patients with primary (AL) amyloidosis where the effectiveness of the reagent could be determined. The use of amyloid-reactive antibodies would represent a novel approach in the treatment of individuals with this invariably fatal disorder.

  • Dobson CM. Getting out of shape. Nature 2002;418(6899):729-730. PubMed: 12181546. Categories: AmyloSENS

    Getting out of shape.

    Nature 2002;418(6899):729-730.

    Getting out of shape.

    Dobson CM.

    Abstract

    Abstract:

    No abstract available.

  • D'Andrea MR, Nagele RG, Wang HY, Peterson PA, Lee DH. Evidence that neurones accumulating amyloid can undergo lysis to form amyloid plaques in Alzheimer's disease. Histopathology 2001;38(2):120-134. PubMed: 11207825. Categories: AmyloSENS

    Evidence that neurones accumulating amyloid can undergo lysis to form amyloid plaques in Alzheimer's disease.

    Histopathology 2001;38(2):120-134.

    Evidence that neurones accumulating amyloid can undergo lysis to form amyloid plaques in Alzheimer's disease.

    D'Andrea MR, Nagele RG, Wang HY, Peterson PA, Lee DH.

    Abstract

    Abstract:

    AIMS: Amyloid has recently been shown to accumulate intracellularly in the brains of patients with Alzheimer's disease (AD), yet amyloid plaques are generally thought to arise from gradual extracellular amyloid deposition. We have investigated the possibility of a link between these two apparently conflicting observations. METHODS AND RESULTS: Immunohistochemistry and digital image analysis was used to examine the detailed localization of beta-amyloid(42) (A beta 42), a major component of amyloid plaques, in the entorhinal cortex and hippocampus of AD brains. A beta 42 first selectively accumulates in the perikaryon of pyramidal cells as discrete, granules that appear to be cathepsin D-positive, suggesting that they may represent lysosomes or lysosome-derived structures. AD brain regions abundantly populated with pyramidal neurones exhibiting excessive A beta 42 accumulations also contained evidence of neuronal lysis. Lysis of these A beta 42-burdened neurones apparently resulted in a local, radial dispersion of their cytoplasmic contents, including A beta 42 and lysosomal enzymes, into the surrounding extracellular space. A nuclear remnant was found at the dense core of many amyloid plaques, strengthening the idea that each amyloid plaque represents the end product of a single neuronal cell lysis. The inverse relationship between the amyloid plaque density and pyramidal cell density in the AD brain regions also supports this possibility, as does the close correlation between plaque size and the size of local pyramidal cells. CONCLUSIONS: Our findings suggest that excessive intracellular accumulation of A beta 42-positive material in pyramidal cells can result in cell lysis, and that cell lysis is an important source of amyloid plaques and neuronal loss in AD brains.

  • Wall J, Schell M, Hrncic R, Macy S, Wooliver C, Wolfenbarger D, Murphy C, Donnell R, Weiss D T, Solomon A. Treatment of amyloidosis using an anti-fibril monoclonal antibody: Preclinical efficacy in a murine model of AA-amyloidosis. In: Bély M, Apáthy A (eds). Amyloid and Amyloidosis. The Proceedings of the IX International Symposium on Amyloidosis. 2001; Budapest, Hungary: David Apáthy, pp. 158-160. Categories: AmyloSENS

    Treatment of amyloidosis using an anti-fibril monoclonal antibody: Preclinical efficacy in a murine model of AA-amyloidosis.

    In: Bély M, Apáthy A (eds). Amyloid and Amyloidosis. The Proceedings of the IX International Symposium on Amyloidosis. 2001; Budapest, Hungary: David Apáthy, pp. 158-160.

    Treatment of amyloidosis using an anti-fibril monoclonal antibody: Preclinical efficacy in a murine model of AA-amyloidosis.

    Wall J, Schell M, Hrncic R, Macy S, Wooliver C, Wolfenbarger D, Murphy C, Donnell R, Weiss D T, Solomon A.

    Abstract

    Abstract:

    No abstract available.

  • Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, Connor K, Hatcher J, Hope C, Gordon M, Arendash GW. Abeta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature 2000;408(6815):982-985. PubMed: 11140686. Categories: AmyloSENS

    Abeta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease.

    Nature 2000;408(6815):982-985.

    Abeta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease.

    Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, Connor K, Hatcher J, Hope C, Gordon M, Arendash GW.

    Abstract

    Abstract:

    Vaccinations with amyloid-beta peptide (A beta) can dramatically reduce amyloid deposition in a transgenic mouse model of Alzheimer's disease. To determine if the vaccinations had deleterious or beneficial functional consequences, we tested eight months of A beta vaccination in a different transgenic model for Alzheimer's disease in which mice develop learning deficits as amyloid accumulates. Here we show that vaccination with A beta protects transgenic mice from the learning and age-related memory deficits that normally occur in this mouse model for Alzheimer's disease. During testing for potential deleterious effects of the vaccine, all mice performed superbly on the radial-arm water-maze test of working memory. Later, at an age when untreated transgenic mice show memory deficits, the A beta-vaccinated transgenic mice showed cognitive performance superior to that of the control transgenic mice and, ultimately, performed as well as nontransgenic mice. The A beta-vaccinated mice also had a partial reduction in amyloid burden at the end of the study. This therapeutic approach may thus prevent and, possibly, treat Alzheimer's dementia.

  • Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, Chishti MA, Horne P, Heslin D, French J, Mount HT, Nixon RA, Mercken M, Bergeron C, Fraser PE, St George-Hyslop P, Westaway D. Abeta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature 2000;408(6815):979-982. PubMed: 11140685. Categories: AmyloSENS

    Abeta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease.

    Nature 2000;408(6815):979-982.

    Abeta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease.

    Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, Chishti MA, Horne P, Heslin D, French J, Mount HT, Nixon RA, Mercken M, Bergeron C, Fraser PE, St George-Hyslop P, Westaway D.

    Abstract

    Abstract:

    Much evidence indicates that abnormal processing and extracellular deposition of amyloid-beta peptide (A beta), a proteolytic derivative of the beta-amyloid precursor protein (betaAPP), is central to the pathogenesis of Alzheimer's disease (reviewed in ref. 1). In the PDAPP transgenic mouse model of Alzheimer's disease, immunization with A beta causes a marked reduction in burden of the brain amyloid. Evidence that A beta immunization also reduces cognitive dysfunction in murine models of Alzheimer's disease would support the hypothesis that abnormal A beta processing is essential to the pathogenesis of Alzheimer's disease, and would encourage the development of other strategies directed at the 'amyloid cascade'. Here we show that A beta immunization reduces both deposition of cerebral fibrillar A beta and cognitive dysfunction in the TgCRND8 murine model of Alzheimer's disease without, however, altering total levels of A beta in the brain. This implies that either a approximately 50% reduction in dense-cored A beta plaques is sufficient to affect cognition, or that vaccination may modulate the activity/abundance of a small subpopulation of especially toxic A beta species.

  • Hrncic R, Wall J, Wolfenbarger DA, Murphy CL, Schell M, Weiss DT, Solomon A. Antibody-mediated resolution of light chain-associated amyloid deposits. Am J Pathol 2000;157(4):1239-1246. PubMed: 11021828. Categories: AmyloSENS

    Antibody-mediated resolution of light chain-associated amyloid deposits.

    Am J Pathol 2000;157(4):1239-1246.

    Antibody-mediated resolution of light chain-associated amyloid deposits.

    Hrncic R, Wall J, Wolfenbarger DA, Murphy CL, Schell M, Weiss DT, Solomon A.

    Abstract

    Abstract:

    Primary light-chain-associated (AL) amyloidosis is characterized by the deposition in tissue of monoclonal light chains as fibrils. With rare exception, this process is seemingly irreversible and results in progressive organ dysfunction and eventually death. To determine whether immune factors can effect amyloid removal, we developed an experimental model in which mice were injected with amyloid proteins extracted from the spleens or livers of patients with AL amyloidosis. Notably, the resultant amyloidomas were rapidly resolved, as compared to controls, when animals received injections of an anti-light-chain monoclonal antibody having specificity for an amyloid-related epitope. The reactivity of this monoclonal antibody was not dependent on the V(L) or C(L) isotype of the fibril, but rather seemed to be directed toward a beta-pleated sheet conformational epitope expressed by AL and other amyloid proteins. The amyloidolytic response was associated with a pronounced infiltration of the amyloidoma with neutrophils and putatively involved opsonization of fibrils by the antibody, leading to cellular activation and release of proteolytic factors. The demonstration that AL amyloid resolution can be induced by passive administration of an amyloid-reactive antibody has potential clinical benefit in the treatment of patients with primary amyloidosis and other acquired or inherited amyloid-associated disorders.

  • Hashizume Y, Wang Y, Yoshida M. Neuropathological study in the central nervous system of centenarians. In: Tauchi H, Sato T, Watanabe T (eds). Japanese Centenarians: Medical Research for the Final Stages of Human Aging. 1999; Institute for Medical Science of Aging, Aichi, Japan:137-154. Categories: AmyloSENS

    Neuropathological study in the central nervous system of centenarians.

    In: Tauchi H, Sato T, Watanabe T (eds). Japanese Centenarians: Medical Research for the Final Stages of Human Aging. 1999; Institute for Medical Science of Aging, Aichi, Japan:137-154.

    Neuropathological study in the central nervous system of centenarians.

    Hashizume Y, Wang Y, Yoshida M.

    Abstract

    Abstract:

    No abstract available.

  • Tauchi H, Sato T. Autopsy findings: outline and generational differences. In: Tauchi H, Sato T, Watanabe T (eds). Japanese Centenarians: Medical Research for the Final Stages of Human Aging. 1999; Institute for Medical Science of Aging, Aichi, Japan:132-136. Categories: AmyloSENS

    Autopsy findings: outline and generational differences.

    In: Tauchi H, Sato T, Watanabe T (eds). Japanese Centenarians: Medical Research for the Final Stages of Human Aging. 1999; Institute for Medical Science of Aging, Aichi, Japan:132-136.

    Autopsy findings: outline and generational differences.

    Tauchi H, Sato T.

    Abstract

    Abstract:

    No abstract available.

  • Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999;400(6740):173-177. PubMed: 10408445. Categories: AmyloSENS

    Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse.

    Nature 1999;400(6740):173-177.

    Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse.

    Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P.

    Abstract

    Abstract:

    Amyloid-beta peptide (Abeta) seems to have a central role in the neuropathology of Alzheimer's disease (AD). Familial forms of the disease have been linked to mutations in the amyloid precursor protein (APP) and the presenilin genes. Disease-linked mutations in these genes result in increased production of the 42-amino-acid form of the peptide (Abeta42), which is the predominant form found in the amyloid plaques of Alzheimer's disease. The PDAPP transgenic mouse, which overexpresses mutant human APP (in which the amino acid at position 717 is phenylalanine instead of the normal valine), progressively develops many of the neuropathological hallmarks of Alzheimer's disease in an age- and brain-region-dependent manner. In the present study, transgenic animals were immunized with Abeta42, either before the onset of AD-type neuropathologies (at 6 weeks of age) or at an older age (11 months), when amyloid-beta deposition and several of the subsequent neuropathological changes were well established. We report that immunization of the young animals essentially prevented the development of beta-amyloid-plaque formation, neuritic dystrophy and astrogliosis. Treatment of the older animals also markedly reduced the extent and progression of these AD-like neuropathologies. Our results raise the possibility that immunization with amyloid-beta may be effective in preventing and treating Alzheimer's disease.

  • Badman MK, Pryce RA, Charge SB, Morris JF, Clark A. Fibrillar islet amyloid polypeptide (amylin) is internalised by macrophages but resists proteolytic degradation. Cell Tissue Res 1998;291(2):285-294. PubMed: 9426315. Categories: AmyloSENS

    Fibrillar islet amyloid polypeptide (amylin) is internalised by macrophages but resists proteolytic degradation.

    Cell Tissue Res 1998;291(2):285-294.

    Fibrillar islet amyloid polypeptide (amylin) is internalised by macrophages but resists proteolytic degradation.

    Badman MK, Pryce RA, Charge SB, Morris JF, Clark A.

    Abstract

    Abstract:

    Pancreatic islet amyloid, formed from islet amyloid polypeptide, is found in 96% of Type II (non-insulin-dependent) diabetic patients. Islet amyloidosis is progressive and apparently irreversible. Fibrils immunoreactive for islet amyloid polypeptide are found in macrophages associated with amyloid, suggesting that deposits can be phagocytosed. To determine the mechanism for the recognition and internalisation of fibrils, mouse peritoneal macrophages were cultured with fibrillar synthetic human islet amyloid polypeptide. Fibrils did not exert a cytotoxic effect over 72 h of culture. The uptake and degradation of fibrils was analysed by quantitative light-and electron-microscopic immunocytochemistry and immunoreactivity was detectable in 86+/-3% cells within 6 h of culture. Neither polyinosinic acid (200 microg/ml) nor nocodazole (10 microg/ml) inhibited fibril uptake, suggesting that internalisation is not blocked by poly-ions and is independent of microtubule assembly. Inhibition of pseudopodia formation by cytochalasin B blocked fibriI uptake. Fibril aggregates became condensed in lysosomes to form protofilaments and were resistant to intracellular proteolysis. Fibrils can be phagocytosed by macrophages in vitro but amyloid-associated factors may block the recognition of fibrils in vivo preventing the removal of islet amyloid in diabetes.

  • Paresce DM, Chung H, Maxfield FR. Slow degradation of aggregates of the Alzheimer's disease amyloid beta-protein by microglial cells. J Biol Chem 1997;272(46):29390-29397. PubMed: 9361021. Categories: AmyloSENS

    Slow degradation of aggregates of the Alzheimer's disease amyloid beta-protein by microglial cells.

    J Biol Chem 1997;272(46):29390-29397.

    Slow degradation of aggregates of the Alzheimer's disease amyloid beta-protein by microglial cells.

    Paresce DM, Chung H, Maxfield FR.

    Abstract

    Abstract:

    Microglia are immune system cells associated with senile plaques containing beta-amyloid (Abeta) in Alzheimer's disease. Although microglia are an integral part of senile plaques, their role in the development of Alzheimer's disease is not known. Because microglia are phagocytic cells, it has been suggested that microglia may function as plaque-attacking scavenger cells. Microglia bind and internalize microaggregates of Abeta that resemble those present in dense Alzheimer's disease plaques. In this study, we compared the degradation by microglia of Abeta microaggregates with the degradation of two other proteins, acetylated low density lipoprotein and alpha2-macroglobulin. We found that the majority of the internalized Abeta in microaggregates was undegraded 72 h after uptake, whereas 70-80% of internalized acetylated low density lipoprotein or alpha2-macroglobulin was degraded and released from cells in trichloroacetic acid-soluble form after 4 h. In the continued presence of fluorescent Abeta microaggregates for 4 days, microglia took up huge amounts of Abeta and became engorged with undigested material. These data suggest that microglia can slowly degrade limited amounts of Abeta plaque material, but the degradation mechanisms can be overwhelmed by larger amounts of Abeta.

  • Lorenzo A, Razzaboni B, Weir GC, Yankner BA. Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus. Nature 1994;368(6473):756-760. PubMed: 8152488. Categories: AmyloSENS

    Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus.

    Nature 1994;368(6473):756-760.

    Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus.

    Lorenzo A, Razzaboni B, Weir GC, Yankner BA.

    Abstract

    Abstract:

    The 37-amino-acid polypeptide amylin is the principal constituent of the amyloid deposits that form in the islets of Langerhans in patients with type-2 diabetes mellitus, but its role in the pathogenesis of this disease is unresolved. In view of the fact that the beta-amyloid protein that forms fibrils in Alzheimer's disease is toxic to neurons, we have investigated whether amylin fibrils could be toxic to pancreatic islet cells. We show here that human amylin is toxic to insulin-producing beta-cells of the adult pancreas of rats and humans. This toxicity is mediated by the fibrillar form of the amylin peptide and requires direct contact of the fibrils with the cell surface. The mechanism of cell death involves RNA and protein synthesis and is characterized by plasma membrane blebbing, chromatin condensation and DNA fragmentation, indicating that amylin induces islet cell apoptosis. These findings indicate that amylin fibril formation in the pancreas may cause islet cell dysfunction and death in type-2 diabetes mellitus.