Characterizing amyloid precursor protein (APP) signaling in neural stem cells.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder that is characterized by irreversible and progressive loss of money and deterioration of higher cognitive functions. The brain of an individual with AD exhibits extracellular senile plaques of aggregated amyloid-beta-peptide AB, intracellular neurofibrilary tangles (NFTs) that contain hyperphosphorylated tau protein (a microtubute associated protein) and a profound loss of basal forebrain cholinergic neurons that innervate the hippocampus and the neocortex. Our observation that the NGF receptor TRKA os downregulated in AD brain led to our suggestion that an imbalance of neurotrophin receptor signalling may be involved in AD. AD appears to have a heterogeneous etiology and can be caused by mutations in the amyloid precursor protein (APP)gene on chromosome-21, the presenilin-1 (PS-1) gene on chromosome-14, and presenilin-2 (PS-2) gene on chromosome-1. Proteolytic processing of APP generates the amyloid-beta peptide (AB) and has been implicated in the pathogenesis of AD. APP fragments, including AB and APP's C-termial fragments (CTFs) or APP's intracellular domains (AICDs), have been reported to cause apoptosis. Mutations in the APP encoding gene and also in PS-1/2, which lead to early-onset AD, are associated with excess AB deposition in the brains of AD patient suggesting that the depositon of AB is a central disease-causing evant. However, the physiological function of APP and whether this function is related to the proteolytic processing of APP remains unclear. Moreover, the mechanism for the degeneration of nerve cells and synaptic connections that underlies the emergence of dementia, in particular in sporadic AD, is still unknown[1,2]RG 147/0