Comprehensive insights into Alzheimer's disease: Amyloid-β pathology, tau dysfunction, and neurodegenerative mechanisms.

Abstract

Alzheimer's Disease is a terminal, progressive neurodegenerative illness that destroys memory and thought process. The histological hallmark of AD are plaques, found outside of neurons, comprised of amyloid- (A) peptides, and neurofibrillary tangles (NFTs) found within neurons and composed of hyperphosphorylated tau protein. These pathologies of AD cause loss of synaptic function leading to neuronal cell damage and death predominantly in the hippocampus and cerebral cortex. A40 and A42 peptides are generated from the cleavage of amyloid precursor protein (APP) by both-and -secretases although A42 has been reported as more toxic. These oligomers and aggregates of A can reduce synaptic function and also stimulate glial cells, causing oxidative stress and neuroinflammation. Tau is a microtubule-associated protein that keeps the cytoskeleton stable and the cell transportation functioning; during the hyperphosphorylation of tau protein it is released from the microtubules where it aggregates forming NFTs. Once formed the pathological tau can propagate from cell to cell, driving further disease processes. Both A and tau protein have shown synergy to each other; with Amyloid-beta being able to increase tau toxicity to a much greater degree than Amyloid-beta alone. Neuroinflammation continually occurring over many years elevates neurodegeneration by inducing a toxic environment and preventing the removal of damaged proteins from the brain. Some risks associated with the development of Alzheimer's disease (AD) are modifiable (obesity, diabetes, cigarette smoking) while other risks are non-modifiable (age, genetics).