New insights on Alzheimer's disease

Alzheimer's disease (AD), the most common age-associated dementing disorder, is clincopathologically manifested by progressive cognitive dysfunction concomitant with the accumulation of senile plaques (SP). SP is consisting of amyloid-β (Aβ) peptides and neurofibrillary tangles (NFTs) of hyper-phosphorylated tau (p-tau) protein aggregates in the brain of affected individuals. Lipid rafts promote interaction of the amyloid precursor protein (APP) with the β-secretase enzyme responsible for generation of the Aβ peptides. Fibrillar Aβ oligomers, which have been shown to correlate with the onset and severity of AD, bind preferentially to cells and neurons expressing cellular prion protein (PrPC). The binding of Aβ oligomers to cell surface PrPC, as well as their downstream activation of Fyn kinase, was dependent on the integrity of cholesterol-rich lipid rafts. Rafts also regulate cholinergic signaling as well as acetylcholinesterase and Aβ interaction. Such major lipid raft components as cholesterol and ganglioside (GM1) have been directly implicated in pathogenesis of the disease. Perturbation of lipid raft integrity can also affect various signaling pathways leading to cellular death and AD.In this review, I will discuss the more recent findings on the biopathological mechanisms, candidate bio-markers, and therapeutic interventions of the elusive AD.