E. Eitan, E. Tichon, A. Gazit, D. Gitler, S. Slavin, E. Priel

Telomerase is expressed in neonatal brains and also in distinct regions of adult brain. Telomerase was shown to protect developing neurons from apoptosis. Telomerase transgenic mice demonstrated significant resistance to ischemic brain injury and N-methyl-D-aspartic acid (NMDA) neurotoxicity. Hence, we and other hypothesized that increasing telomerase expression by pharmaceutical compounds may protect brain cells from death caused by damaging agents. This study demonstrates the expression and activity levels of telomerase in the adult mouse brain and the ability of novel compound, AGS-499, to increase telomerase activity and expression in the mice forebrain and to exert neuroprotection. We found that telomerase is present in adult mice neurons and it activity is regulated by it inner cellular localization and alternative splicing. Following AGS-499 injection, a significant (3 fold), transient increase in telomerase activity, telomerase reverse transcriptase (TERT) protein and TERT mRNA expression were detected in the forebrain, in a time and dose dependent manner. Treatment with AGS- 499, prior to systemic injection of NMDA, increased the survival rate and decreased the seizures of the NMDA injected mice. AGS treatment significantly delayed ALS mouse model (SOD1G93A) disease onset and significant prolong their life span (18 day) in a dose dependent manner. Moreover, TERT expression is reduced with the disease progression in the brainstem and spinal cord. We suggest that TERT serve as a surviving enzyme in the CNS by a non canonical function and controlled and transient increase of telomerase expression and activity in the brain by AGS 499 may have a potential therapeutic effect in neurodegenerative diseases and other brain disorders

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