Major characteristics of Alzheimer's disease (AD) are synaptic loss, cholinergic dysfunction, and abnormal protein depositions in the brain. The amyloid β-peptide (Aβ), a proteolytic fragment of amyloid β precursor protein (APP), aggregates to form neuritic plaques and has a causative role in AD. A present focus of AD research is to develop safe Aβ-lowering drugs. A selective acetylcholinesterase inhibitor, phenserine, in current human trials lowers both APP and Aβ. Phenserine is dose-limited in animals by its cholinergic actions; its cholinergically inactive enantiomer, posiphen (+)-[phenserine], was assessed. In cultured human neuroblastoma cells, posiphen, like phenserine, dose- and time-dependently lowered APP and Aβ levels by reducing the APP synthesis rate. This action translated to an in vivo system. Posiphen administration to mice (7.5-75 mg/kg daily, 21 consecutive days) significantly decreased levels of total APP (tissue mass-adjusted) in a dose-dependent manner. Aβ40 and Aβ42 levels were significantly lowered by posiphen (≥15 mg/kg) compared with controls. The activities of α-, β-, and γ-secretases were assessed in the same brain samples, and β-secretase activity was significantly reduced. Posiphen, like phenserine, can lower Aβ via multiple mechanisms and represents an interesting drug candidate for AD treatment.
|Original language||English (US)|
|Number of pages||11|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Jan 5 2007|
ASJC Scopus subject areas
- Molecular Medicine