Amyloid-beta protein clearance and degradation (ABCD) pathways and their role in Alzheimer's disease

Abstract

Amyloid-β proteins (Aβ) of 42 (Aβ42) and 40 aa (Aβ40) accumulate as senile plaques (SP) and cerebrovascular amyloid protein deposits that are defining diagnostic features of Alzheimer's disease (AD). A number of rare mutations linked to familial AD (FAD) on the Aβ precursor protein (APP), Presenilin-1 (PS1), Presenilin- 2 (PS2), Adamalysin10, and other genetic risk factors for sporadic AD such as the ε4 allele of Apolipoprotein E (ApoE-ε4) foster the accumulation of Aβ and also induce the entire spectrum of pathology associated with the disease. Aβ accumulation is therefore a key pathological event and a prime target for the prevention and treatment of AD. APP is sequentially processed by β-site APP cleaving enzyme (BACE1) and γ-secretase, a multisubunit PS1/PS2-containing integral membrane protease, to generate Aβ. Although Aβ accumulates in all forms of AD, the only pathways known to be affected in FAD increase Aβ production by APP gene duplication or via base substitutions on APP and γ-secretase subunits PS1 and PS2 that either specifically increase the yield of the longer Aβ42 or both Aβ40 and Aβ42. However, the vast majority of AD patients accumulate Aβ without these known mutations. This led to proposals that impairment of Aβ degradation or clearance may play a key role in AD pathogenesis. Several candidate enzymes, including Insulin-degrading enzyme (IDE), Neprilysin (NEP), Endothelin-converting enzyme (ECE), Angiotensin converting enzyme (ACE), Plasmin, and Matrix metalloproteinases (MMPs) have been identified and some have even been successfully evaluated in animal models. Several studies also have demonstrated the capacity of γ-secretase inhibitors to paradoxically increase the yield of Aβ and we have recently established that the mechanism is by skirting Aβ degradation. This review outlines major cellular pathways of Aβ degradation to provide a basis for future efforts to fully characterize the panel of pathways responsible for Aβ turnover.

Fig. 1. Key APP processing pathways

The neuronal form of APP is a type-1 integral-membrane glycoprotein of 695 aa with a large ectodomain a single transmembrane domain and a short intracellular domain (Blue box). A group of metalloproteases named α-secretase cleave APP inside the Aβ sequence (violet triangle) between residues 16 and 17 to produce a secreted fragment of 612 aa, sAPPα, and a cellular fragment of 83 aa - CTFα. This is the major pathway and accounts for 80–90% of APP turnover. In the amyloidogenic pathway, BACE1 (β) cleaves APP to the secreted fragment, sAPPβ (red diamond), of 596 aa and membrane-bound fragment CTFβ of 99 aa. Which in turn is processed to Aβ by γ-secretase. Aβ is degraded and cleared by multiple known and unknown pathways as shown.

Fig. 2. Model showing the cell biology of Aβ production and degradation

APP is synthesized in the ER and gets transported to the Golgi apparatus where it is packaged to vesicles (orange circles) for delivery to the cell surface (Step 1.). APP that does not get processed by the α-secretase in the secretary pathway is internalized into endosomes (Large blue circles), which are acidic compartments (Steps 2 and 3). BACE1 cleaves APP in the endosome to generate CTFβ, which is then processed to Aβ by γ-secretase within the endosome (Step 4). In neurons, a large fraction of the Aβ generated in this compartment is degraded by ECE and unknown proteases (Step 5). Aβ that escapes this pathway may be transported to the lysosome and degraded (Step 6). Alternatively, Aβ containing recycling vesicles (small blue circles) can be recycled to the cell surface either via the Golgi apparatus (Steps 7 and 8)or directly from the endosome to the cell surface (Step 9). Aβ may be released from recycling vesicles to the UPS for degradation (Step 10) or get degraded at the cell surface by other known pathways such as NEP, IDE, MMP-9 or by other unidentified pathways. The Aβ that escapes degradation may be drained into the cerebrospinal fluid or cleared into the lymphatic or vascular circulation. Failure of all these redundant turnover mechanisms will lead to accumulation and aggregation of Aβ into SP and as CVAP.

Fig. 3. Sequence variants of endothelin converting enzyme

ECE-1 is a type-II membrane protein with a variable N-terminal intracellular (IC) domain, and conserved transmembrane (TMD) and extracellular (Lumen) domains [153]. Through multiple alternate promoters, at least four isoforms of ECE-1 have been identified, each with unique intracellular domains that determine subcellular localization and tissue distribution, Isoforms 1a and 1c are primarily localized in the plasma membrane, whereas isoform 1b and 1d are predominantly located in late endosomes/multivesicular bodies and recycling endosomes, respectively [70, 119, 154].