The neuroprotective effect of AGS-499 compound depends on telomerase expression

E. Eitan, E. Tichon, D. Gitler, E. Priel

Research output: Contribution to journalMeeting Abstract

Abstract

Telomerase is expressed in neonatal brains and in distinct
regions of adult brain and 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 ability of novel compound, AGS-499, to
increase telomerase activity and expression in the mice
forebrain and to exert neuroprotection. 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, cerebellum, brainstem and spinal cord, in a time
and dose dependent manner. AGS-499 enhances telomerase
activity in the motor neuron cell line NSC-34 and increases
their cell viability after H2O2 treatment. However, in NSC34TERT-GFP and in cells transfected with TERT shRNA
the AGS compound did not increase the survival of cells
following H2O2 treatment and telomerase expression was
not enhanced in cells that overexpressed TERT. These
results suggest that the neuroprotective effect of AGS-499
depends on telomerase expression. In-vivo treatments 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 serves as a surviving enzyme in the CNS
therefore 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
Original languageEnglish GB
Pages (from-to)S30-S30
Number of pages132
JournalJournal of Molecular Neuroscience
Volume48
Issue number1
DOIs
StatePublished - Nov 2012

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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