Program

SY54-3

Posiphen – a new experimental drug to understand and mitigate age-related neurodegenerative disorders

[Speaker] Nigel H. Greig:1
1:Intramural Research Program, National Institute on Aging, National Institutes of Health, USA

A commonality between numerous neurodegenerative disorders is the generation of different self-aggregating proteins/peptides whose presence and accumulation both define the disease and drive neurotoxic pathological cascades that result in disease progression. These proteins include amyloid-β peptide (Aβ) generated from amyloid precursor protein (APP) in Alzheimer's disease (AD), α-synuclein (α-syn) in Parkinson's disease (PD), Tau in tauopathies and prions in transmissible spongiform encephalopathies. The oligomerization/self-aggregation and resulting neurotoxicity of such proteins is generally concentration dependent, and agents that selectively reduce their rate of synthesis in a well-tolerated manner possess therapeutic potential. Posiphen ((+)-N-phenylcarbamoyleseroline tartrate) was selected from a screen of 144 analogues generated to lower APP mRNA translation at the level of its 5’-untranslated region. In neuronal cellular studies, the brain of wild type and AD transgenic (APP+PS1) mice, and in CSF of humans with mild cognitive impairment (MCI), Posiphen lowers APP as well as Aβ levels without adverse actions, and is hence being evaluated as a new treatment strategy for AD and MCI. The molecular machinery underpinning Posiphen’s repression of APP mRNA translation appears to be relevant to α-syn (Friedlich et al., Mol Psychiatry 12:222, 2007) and, quite possibly, other proteins. In neuronal cellular and in vivo studies, Posiphen lowers α-syn levels and provides neurotrophic actions – augmenting neurogenesis. Posiphen hence possesses potential therapeutic actions across neurodegenerative disorders, including AD, PD and ischemic stroke.
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