Amyloid precursor protein processing and Alzheimer's disease

Abstract

Alzheimer's disease (AD), the leading cause of dementia worldwide, is characterized by the accumulation of the β-amyloid peptide (Aβ) within the brain along with hyperphosphorylated and cleaved forms of the microtubule-associated protein tau. Genetic, biochemical, and behavioral research suggest that physiologic generation of the neurotoxic Aβ peptide from sequential amyloid precursor protein (APP) proteolysis is the crucial step in the development of AD. APP is a single-pass transmembrane protein expressed at high levels in the brain and metabolized in a rapid and highly complex fashion by a series of sequential proteases, including the intramembranous γ-secretase complex, which also process other key regulatory molecules. Why Aβ accumulates in the brains of elderly individuals is unclear but could relate to changes in APP metabolism or Aβ elimination. Lessons learned from biochemical and genetic studies of APP processing will be crucial to the development of therapeutic targets to treat AD.

Figure 1

Pathology of Alzheimer’s disease. (a, b) Brain sections from a patient with dementia are stained with silver, revealing neuritic plaques in panel a and a neurofibrillary tangle in panel b. The plaques in panel a consist of an amorphous reddish protein (Aβ) with dystrophic neurites (yellow arrows, dark black material ). (c) An Aβ plaque stained with an anti-Aβ antibody (red ) shows infiltrating microglia stained with an IBA1 antibody ( green). Each line is 40 microns.

Figure 2

Sequential cleavage of the amyloid precursor protein (APP) occurs by two pathways. (a) The APP family of proteins has large, biologically active, N-terminal ectodomains as well as a shorter C-terminus that contains a crucial Tyrosine–Glutamic Acid-Asparagine-Proline-Threonine-Tyrosine (YENPTY) protein-sorting domain to which the adaptor proteins X11 and Fe65 bind. The Aβ peptide starts within the ectodomain and continues into the transmembrane region (red ). (b) Nonamyloidogenic processing of APP involving α-secretase followed by γ-secretase is shown. (c) Amyloidogenic processing of APP involving BACE1 followed by γ-secretase is shown. Both processes generate soluble ectodomains (sAPPα and sAPPβ) and identical intracellular C-terminal fragments (AICD). Figure 2 was adapted from Thinakaran G, Koo EH. 2008 Amyloid precursor protein trafficking, processing, and function. J. Biol. Chem. 283:29615–19

Figure 3

APP trafficking in neurons. Newly synthesized APP ( purple) is transported from the Golgi down the axon (1) or into a cell body endosomal compartment (2). After insertion into the cell surface, some APP is cleaved by α-secretase (6) generating the sAPPα fragment, which diffuses away ( green), and some is reinternalized into endosomes (3), where Aβ is generated (blue). Following proteolysis, the endosome recycles to the cell surface (4), releasing Aβ(blue) and sAPPβ. Transport from the endosomes to the Golgi prior to APP cleavage can also occur, mediated by retromers (5).

Figure 4

Aβ toxicity. An equilibrium between several species of extracellular and intracellular Aβ, including monomeric, oligomeric, and fibrillar forms, causes toxicity through several mechanisms including microglial infiltration, the generation of reactive oxygen species, and synaptic damage. Neurofibrillary tangles are generated by Aβ-induced tau phosphorylation and cleavage. Enzymes activated directly by extracellular Aβ include GSK3β, Cdk5, and multiple caspases, which activate tau cleavage and phosphorylation among their many deleterious effects.