Amyloid plaques, hallmark neuropathological lesions in Alzheimer's disease (AD) brain, are composed of the beta-amyloid peptide (Abeta). Evidence suggests that Abeta is central to the pathophysiology of AD and likely triggers this neurodegenerative disorder.
Amyloid beta is processed from the Type 1 transmembrane protein -Amyloid precursor protein (APP) by beta secretase (BACE1) and the gamma secretase complex comprising of Presenilin1/2. Mutations in APP, BACE1 and Presenilins are found in cases of familial Alzheimer's disease and result in the synthesis of toxic plaque forming amyloid beta peptide - Abeta42. The mechanism of Abeta mediated toxicity appears to involve a destabilization of neuronal Ca2+ homeostasis. Abnormal Ca2+ influx results in the aberrant activation of Calpain, which contributes to the phosphorylation of the microtubule associated protein Tau via the CDK5 pathway. In addition, oxidative stress associated with the accumulation of Abeta activates several kinases, including MAP kinases,resulting in the phosphorylation of Tau.
Paired helical filaments (PHFs) are the structural constituents of neurofibrillary tangles in Alzheimer's disease and are composed of hyperphosphorylated forms of Tau. Pathological hyperphosphorylation of tau is believed to be an important contributor to the destabilization of microtubules and their subsequent disappearance from tangle-bearing neurons in Alzheimer's disease.
The Amyloid processing pathway highlights the important molecular events that lead up to neuronal death in Alzheimer's disease.