Active Aß Immunization Reverses (Some) Neuritic Pathology

Posted by Michael Rae on June 27, 2010 | Chief Science Officer's Team

A variety of extracellular aggregates accumulate in the aging body, and strong evidence exists for their contribution to age-related morbidity and pathology. This makes them targets for regenerative engineering: the rescue of youthful tissue function through the restoration of structure from such damage. In the case of extracellular aggregates, the most promising biomedical approach is their clearance with targeted immunotherapy.

The most well-characterized such extracellular aggregate is beta-amyloid protein (Aß), which accumulates in the aging brain of nondemented adults (with ~20-30% of older seemingly-healthy brains exhibiting significant plaque deposition (1) and a rising but yet-uncertain accumulation  of soluble, intraneuronal Aß species), and which is strongly linked through several lines of evidence with Alzheimer disease (AD). It is also far and away the regenerative engineering target for which a platform therapy in the most advanced state of clinical development, with a recent review (2) counting “at least seven passive Aß immunotherapies ... now in clinical trials in patients with mild to moderate AD [and] several second-generation active Aß vaccines … also in early clinical trials”.(2)

Much of this excitement is due to the results of early trials the original Elan Abeta vaccine, AN1792, which was late in a Phase IIA randomized, placebo-controlled trial when it was shut down due to infrequent (6% of patients) encephalomyelitis. Preliminary analysis  appeared to document a disease-modifying effect on disease progression in  the subset (19.7%) of patients administered the vaccine who mounted a significant antibody response to the vaccine. In such subjects, anti-Aß vaccination led to with decelerated decline in cognitive function on a subset of memory tests and lower cerebrospinal fluid phosphorylated tau species relative to placebo; moreover, the brains of autopsied subjects exhibited a nearly complete absence of  neuritic plaque and soluble Aß, with a high frequency of a ‘moth-eaten’ morphology among the remaining plaques, along with reduced neuronal loss and extensive clearance of tau-containing neurites, although more mature tau pathology (neurofibrillary tangles and neuropil threads) appeared to be unaffected ((3-5), and see previous postings). More recently (6), a long-term (4.6 y) followup of 129 surviving immunized patients and paired caregivers found that the 25 responder subjects exhibited slower  decline on the Disability Assessment for Dementia and Dependence Scale. Additionally, while hippocampal volume was low at baseline in the AN1792 group, it stabilized several months after vaccination and remained steady during the 4.6 y followup, while adjuvant-only controls suffered ongoing declines.(6)

However, the brains of AD exhibit a range of pathology beyond the characteristic Aß plaques, tau deposits, and neuronal loss. As reviewed in (2), "the neurodegenerative process in AD might be initiated by damage to the synaptic terminals. Indeed, early synaptic pathology has been postulated to lead to axonal abnormalities, dendritic spine and dendrite atrophy and, eventually, neuronal loss." And as noted in a recent report,(7) "the neurites within the dense-core amyloid plaques in the human Alzheimer’s disease brain have a more abnormal trajectory compared to the neurites outside the plaques, and also compared to the neurites in the brain of non-demented controls ... [We developed the] neurite curvature ratio as a quantitative measure of neuritic abnormalities ... [W]e have previously shown that plaque-induced neuritic curvature can potentially contribute to the cognitive deficits seen in Alzheimer’s disease by disrupting the cortical synaptic integration ([(8,9) below])".

Recently, scientists from the latter group collaborated on a new report to probe the effect of active Aß vaccination on these neuritic dystrophies. The results were promising.

... Hippocampal sections from five patients with Alzheimer's disease enrolled in the AN1792 Phase 2a trial [3 responders, 1 non-, 1 probable non-] were compared with those from 13 non-immunized Braak stage- and age- matched patients with Alzheimer's disease, and eight age-matched non-demented controls. ...

Amyloid load and density of dense-core plaques were decreased in the immunized group compared to non-immunized patients (P < 0.01 and P < 0.001, respectively) ... Compared to non-immunized patients, dense-core plaques remaining after immunization had similar degree of astrocytosis (P = 0.6060), more embedded dystrophic neurites (P < 0.0001) and were more likely to have mitochondrial accumulation (P < 0.001). ... 

In immunized patients, however, the [neurite] curvature ratio was normalized when compared to non-immunized patients (P < 0.0001), and not different from non-demented controls.  .... This result is not merely due the existence of fewer plaques in the immunized Alzheimer’s disease group, because in the plaque-based analysis performed subsequently, curvature ratios of both neurites located close to and far from dense-core plaques also were significantly lower in AN1792-treated patients, compared to the non-immunized patients. In fact, unlike these results in the non-immunized group [in whom "neurites close to dense-core plaques (within 50 microm) were more abnormal than those far from plaques"], in the immunized patients both curvature ratios were almost identical  ...  and both were straighter compared to the non-immunized patients (P < 0.0001) ... [This] difference was preserved across different plaque size intervals. ... [Thus,] the significant difference observed in the curvature ratio close to plaques between both Alzheimer’s disease groups is not merely due to the plaques from the immunized group being smaller and exerting less ‘mass effect’ on surrounding neurites... [but] unequivocally points to the reduction of an abnormal neurite morphology otherwise existing around the dense-core plaques.

Taken together, these results indicate that AN1792 immunization reproduces the beneficial effects on neurite trajectories observed with anti-Aß passive immunization in preclinical studies and further extend previous evidence of anti-Aß immunization-induced improvement in markers of neuronal degeneration in the human Alzheimer’s disease brain.  ... In addition, there was a significant decrease in the density of paired helical filament-1-positive neurons in the immunized group as compared to the non-immunized (P < 0.05), but not in the density of Alz50 or thioflavin-S positive tangles, suggesting a modest effect of anti-amyloid-beta immunization on tangle pathology.

Remarkably, among the immunized patients, both the subject who developed an autoimmune meningoencephalitis and the subject who did not generate ... detectable anti-AN1792 antibody response had the highest densities of Alz50, PHF1 and thioflavin-S positive neurons. Therefore, it is possible that immunization at an earlier stage of the disease ... would have reverted or even prevented the development of neurofibrillary tangles to a greater extent. These findings suggest a link between Aβ and tau, and provide strong support for the amyloid cascade hypothesis, which postulates that Aβ accumulation triggers the onset of Alzheimer’s disease and that tau hyperphosphorylation, subsequent neurofibrillary tangles formation and neuronal death are downstream consequences of the Aβ aggregation ...(7)

As the authors note, while there is evidence that the neuritic abnormalities of AD may contribute to subsequent neurodegeneration and cognitive deficits of the disease, its normalization is unlikely to have reversed all of its downstream effects, and there was no clear evidence that it was directly associated with a slowing of cognitive decline. This is consistent with available evidence from previous reports from animal models, from the AN1792 trial and more recently from the bapineuzumab Phase II trial,(10) and from our knowledge of the pathogenesis of the disease. Whether or not the buildup of Aß aggregates beyond the "threshold of pathology" is indeed the initiating etiopathological lesion in AD (the "amyloid cascade"), there is a great deal of additional pathology involved in clinical AD, including neuron loss, neurofibrillary tangles, aberrant neurogenesis and cell-cycling, inflammation and other abnormalities, and while some of these may well reverse upon removal of Aß aggregates, others (notably neuronal loss) will remain unless removed, repaired, replaced, or rendered harmless by other regenerative engineering platform biomedicines. In the nearer term, prevention of the disease through early use of immunization in prodromal stages or even "normallly" aging adults seems increasingly clearly to be called-for. Fortunately, this position is a emerging as a clear consensus in the AD research field see eg. (2,7)), and  initiatives are underway to design trials  based on biomarkers of the disease before AD or even its late prodromal stages have emerged.

It is, in any event, remarkable that AN1792 was able to so thoroughly normalize a structural deformity in the mature AD brain, further validating the therapeutic platform and encouraging the development of the new generation of Aß immunotherapy.

 

References

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2. Lemere CA, Masliah E. Can Alzheimer disease be prevented by amyloid-beta immunotherapy? Nat Rev Neurol. 2010 Feb;6(2):108-19.  PubMed PMID: 20140000; PubMed Central PMCID: PMC2864089.

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