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Review
. 2013 Oct 8;5(5):46.
doi: 10.1186/alzrt211. eCollection 2013.

The role of APP and BACE1 trafficking in APP processing and amyloid-β generation

Xiaojie Zhang  1 , Weihong Song  1
Affiliations
Review

The role of APP and BACE1 trafficking in APP processing and amyloid-β generation

Xiaojie Zhang et al. Alzheimers Res Ther. .

Abstract

Neuritic plaques in the brain are a major neuropathological hallmark of Alzheimer's disease. They are formed by the deposition and aggregation of extracellular amyloid-β protein (Aβ). Aβ is derived from the sequential cleavage of amyloid-β precursor protein (APP) by β-secretase and γ-secretase. β-Site APP cleaving enzyme 1 (BACE1) functions as the primary, if not sole, β-secretase in vivo and is essential for Aβ production. Regulation of APP processing is a major focus of research into AD pathogenesis. The trafficking systems of APP and its cleavage enzymes are complex. Transporting APP and secretases into the same subcellular organelles facilitates their interaction and favors APP processing. The role of APP and BACE1 trafficking in the amyloidgenic pathway and the underlying mechanisms for Aβ production are discussed in this review. In addition, the distinct mechanisms of amino- and carboxy-terminal Aβ generation are reviewed.

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Figures

Figure 1
Figure 1
β-Amyloid precursor protein processing. β-Amyloid precursor protein (APP) can be cleaved via two pathways, the nonamyloidogenic pathway (left, green) or the amyloidogenic pathway (right, red). Under normal conditions, the majority of APP is cleaved within the amyloid-β (Aβ) domain by α-secretase to produce secreted APP (sAPP)α and membrane-bound C83. C83 can be further cleaved by γ-secretase, producing extracellular fragment p3 and intracellular carboxy-terminal fragment (CTF)γ. In the amyloidogenic pathway, APP is first cleaved by β-secretase to produce sAPPβ and membrane-bound C99. Cleavage of C99 by γ-secretase yields Aβ and intracellular CTFγ. γ-Secretase cleaves APP at multiple sites close to the inner membrane leaflet to produce variants of Aβ peptide with different lengths. The 42 amino acid Aβ peptide, Aβ42 (after γ-cleavage indicated in the figure), is considered the major toxic Aβ in Alzheimer’s disease. Insoluble Aβ is deposited and aggregates to form the core of neuritic plaques in the brain, the pathological hallmark of Alzheimer’s disease.
Figure 2
Figure 2
β-Amyloid precursor protein trafficking. β-Amyloid precursor protein (APP) matures through the constitutive secretory pathway from the endoplasmic reticulum to the plasma membrane (PM). The majority of APP is then quickly internalized into early endosomes, where APP is recycled back to the PM or targeted to the lysosomal degradation pathway. Nonamyloidogenic processing (green) mainly occurs at the cell surface, where α-secretase is particularly enriched. Amyloidogenic processing (red) involves APP trafficking through the secretory and recycling pathways where APP interacts with β- and γ-secretases. Amyloid-β (Aβ) is mainly generated in the trans-Golgi network where the γ-secretase complex is enriched.
Figure 3
Figure 3
Distinctly regulated β-amyloid precursor protein and β-site β-amyloid precursor protein cleaving enzyme 1 trafficking. β-Amyloid precursor protein (APP) and β-site APP cleaving enzyme 1 (BACE1) trafficking is differentially regulated from the site of trans-Golgi network exit, internalization and further sorting into different compartments. Internalization of APP occurs through recruitment of the adaptor-protein complex AP-2 and Dab2 for clathrin-mediated endocytosis. Munc18-interacting protein (Mint; also called X11) is involved in the outward transport of APP from the trans-Golgi network to the plasma membrane. The recycling pathway of BACE1 is mediated by Golgi-localized γ-ear-containing ARF-binding proteins (GGAs). ADP-ribosylation factor-6 (ARF6) mediates sorting of newly internalized BACE1 into Rab5-positive early endosome and GGA3 could modulate BACE1 turnover and stability while sorting it into the lysosome.
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