Leaders in the field of Alzheimer's disease (AD) used to believe that targeting the accumulation of β amyloid (Aβ), a hydrophobic, neurotoxic self-aggregating 40 to 42 amino acid peptide that accumulates preferentially within senile plaques in the brain, would change the course of AD. More recently, a second hypothesis expanded on the Aβ hypothesis by stating that amyloid precursor protein (APP) in the absence of trophic factors is shed from the surface of neuronal cells and processed into an amino terminal fragment (N-APP) that binds to DR6 receptors and induces nerve cell death (A. Nicolaev et al., Vol. 457, 981-990, 2009). Furthermore, the Bredesen Lab identified another factor that is cleaved from the C-terminal end of APP - C31 - and causes nerve cell degeneration and death in tissue culture cells and in transgenic mice (Galvan V. et al., PNAS, Vol. 103, No. 18, 7130-7135, 2006). They could show that over expression of the C31 peptide leads to neuronal degeneration without Ab toxicity and plaque deposition.
Posiphen® inhibits the synthesis of APP which in turn decreases the levels of N-APP, Aβ and C31, all three toxic peptides derived from the precursor protein. Therefore it interferes with a basic pathway that leads to dementia in Down Syndrome, AD and likely other conditions, such as head trauma and stroke. We have substantial data in a number of animal models all showing that Posiphen inhibits APP and therefore one of the major pathways leading to dementia and AD.
We also have data in mildly cognitive impaired patients where 10 days of Posiphen treatment lowers levels of APP, tau and inflammatory factors in the CSF. This human data confirms Posiphen�s mechanism of action in humans and positions the drug for further clinical development.