Neurobiological pathways to Alzheimer's disease: Amyloid-beta, TAU protein or both?

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, including memory loss, behavioral and psychological symptoms and personality changes. The neuropathological hallmarks of AD are the presence of neuritic (senile) plaques (NP) and neurofibrillary tangles (NFT), along with neuronal loss, dystrophic neurites, and gliosis. Neuritic plaques are extracellular lesions and their main constituent is the amyloid-β₄₂ peptide (Aβ₄₂). Neurofibrillary tangles are intracellular lesions that are mainly composed of hyperphosphorylated Tau protein. In this article, we review the major hypotheses concerning the physiopathology of AD, focusing on the β-amyloid cascade as primary events (supported by the "βaptists") and cytoskeletal abnormalities secondary to the hyperphosphorylation of protein Tau (as advocated by the "Tauists"). We further provide an integrative view of the physiopathology of AD.

Keywords: Alzheimer’s disease; Tau protein; amyloid precursor protein; beta amyloid.

Figure 1

The amyloid precursor protein (APP) is a transmembrane protein cleaved by secretase enzymes. In the non-amyloidogenic pathway, APP is cleaved preferentially by a-secretase. In the amyloidogenic pathway, neurotoxic Ab peptides are released after sequential cleavage of APP by b and g-secretases, and further accumulate into oligomeric aggregates.

Figure 2

In AD, there is a reduction in the ability to bind microtubules and promote microtubule assembly. Hyperphosphorylated Tau may contribute to a destabilized microtubule network, impaired axonal transport, and ultimately in neurofibrillary tangle (NFT) formation and neuronal death.