Molecular and Cellular Basis of Neurodegeneration in Alzheimer's Disease

Abstract

The most common form of senile dementia is Alzheimer's disease (AD), which is characterized by the extracellular deposition of amyloid β-peptide (Aβ) plaques and the intracellular formation of neurofibrillary tangles (NFTs) in the cerebral cortex. Tau abnormalities are commonly observed in many neurodegenerative diseases including AD, Parkinson's disease, and Pick's disease. Interestingly, tau-mediated formation of NFTs in AD brains shows better correlation with cognitive impairment than Aβ plaque accumulation; pathological tau alone is sufficient to elicit frontotemporal dementia, but it does not cause AD. A growing amount of evidence suggests that soluble Aβ oligomers in concert with hyperphosphorylated tau (pTau) serve as the major pathogenic drivers of neurodegeneration in AD. Increased Aβ oligomers trigger neuronal dysfunction and network alternations in learning and memory circuitry prior to clinical onset of AD, leading to cognitive decline. Furthermore, accumulated damage to mitochondria in the course of aging, which is the best-known nongenetic risk factor for AD, may collaborate with soluble Aβ and pTau to induce synapse loss and cognitive impairment in AD. In this review, I summarize and discuss the current knowledge of the molecular and cellular biology of AD and also the mechanisms that underlie Aβ-mediated neurodegeneration.

Keywords: APP; Alzheimer’s disease; amyloid β-peptide; neurodegeneration; tau.

Fig. 1

The Regulated Proteolytic Processing of Human β-Amyloid Precursor Protein and the Resulting Cleavage Fragments. (A) Schematic diagram of human β-amyloid precursor protein (APP). The arrows represent the cleavage sites by α-, β-, and γ-secretases. GFLD, growth factor-like domain; CuBD, copper-binding domain; Ac, acidic domain; E2, APP extracellular carbohydrate domain; Aβ, amyloid β-peptide; N-APP, a cleaved N-terminal fragment of APP. (B) Human APP can be processed through either amyloidogenic or non-amyloidogenic pathways. In the amyloidogenic pathway (right), the proteolytic cleavage of the APP by β-secretase produces a large soluble ectodomain of APP (sAPPβ) and a membrane-associated C-terminal fragment (C99). The C99 is subsequently cleaved by γ-secretase, releasing an amyloid β-peptide (Aβ) and an APP intracellular domain (AICD). In a non-amyloidogenic pathway (left), α-secretase-mediated cleavage of the APP generates a soluble ectodomain of APP (sAPPα) and a membrane-tethered C-terminal fragment (C83). The subsequent cleavage of the C83 by γ-secretase gives rise to a P3 peptide and an AICD.

Fig. 2

Human APP Mutations that Cause Familial Alzheimer’s Disease. The amino acid sequence of the amyloid β-peptide (black box) and flanking transmembrane regions is presented; the horizontal arrows indicate the cleavage sites by α-, β-, andγ-secretases. Many missense and deletion mutations within the APP were discovered to cause an inherited form of Alzheimer’s disease.

Fig. 3

The Main Drivers of Neurodegeneration in Alzheimer’s Disease. Neuronal dysfunction and cell death are responsible for the development of Alzheimer’s disease. Accumulating evidence suggests that abnormally elevated tau hyperphosphorylation, pathogenic Aβ oligomers, and mitochondrial dysfunction cooperate to drive the neuronal dysfunction and cell death that underlie cognitive impairment. Although the amyloid hypothesis supports that neurotoxic Aβ primarily induces tau pathology, other proteolytic fragments of the human APP including sAPPβ, N-APP, and AICD, also appear to contribute to tau alterations. In addition, aging, which is tightly associated with mitochondrial dysfunction, can serve as the most significant nongenetic risk factor for Alzheimer’s disease.