beta-Amyloid degradation and Alzheimer's disease

Abstract

Extensive beta-amyloid (A beta) deposits in brain parenchyma in the form of senile plaques and in blood vessels in the form of amyloid angiopathy are pathological hallmarks of Alzheimer's disease (AD). The mechanisms underlying A beta deposition remain unclear. Major efforts have focused on A beta production, but there is little to suggest that increased production of A beta plays a role in A beta deposition, except for rare familial forms of AD. Thus, other mechanisms must be involved in the accumulation of A beta in AD. Recent data shows that impaired clearance may play an important role in A beta accumulation in the pathogenesis of AD. This review focuses on our current knowledge of A beta-degrading enzymes, including neprilysin (NEP), endothelin-converting enzyme (ECE), insulin-degrading enzyme (IDE), angiotensin-converting enzyme (ACE), and the plasmin/uPA/tPA system as they relate to amyloid deposition in AD.

Figure 1

Amyloid cascade hypothesis. Aβ is a normal metabolite which, under physiological conditions, is constantly produced and quickly degraded. Due to genetic defects such as mutations in APP, PS1, or PS2, Aβ production is increased, resulting in familial AD. A similar phenotype can occur with reduction in the Aβ catabolic pathways. Accumulating Aβ will initially oligomerize, gradually form fibrils, and culminate in microscopically visible amyloid plaques. Soluble and fibrillar Aβ and associated plaque proteins are toxic to neurons, resulting in synaptic loss, the formation of neurofibrillary tangles, and eventual neuronal death and AD [5].

Figure 2

Aβ biogenesis. Normally, Aβ is derived from the transmembrane region of amyloid precursor protein (APP) through the sequential cleavage by BACE and γ-secretase. Under physiological conditions, Aβ maintains a steady-state level and is necessary for multiple physiological functions [168]. In AD, Aβ production is increased due to mutations in APP and/or in presenilin (PS1 and PS2) genes. There is an α-secretase cleavage site located between β- and γ-secretase cleavage sites that generates soluble, nonpathogenic peptides [8].

Figure 3

Cleavage sites of Aβ by various enzymes including NEP (N) [14, 169, 170], ECE (E) [17, 169], IDE (I) [170, 171], plasmin (P) [172], and ACE (A) [21]. β: γ-secretase; γ: γ-secretase; 40: Aβ40; 42: Aβ42. Modified from [173].

Figure 4

Possible brain Aβ clearance mechanisms. Aβ peptides may be removed by enzymatic degradation within brain parenchyma [38, 173] or they can be transported through the blood-brain-barrier into the blood or CSF by receptor for advanced glycation endproducts (RAGE), ApoE, β-2-macroglobulin, and the low-density lipoprotein receptor (LRP) [, –176]. The steady-state level of brain Aβ depends upon a balance between production and catabolism. Increased production (like in familial AD) and/or decreased clearance (for most sporadic AD) will result in elevated brain Aβ levels and potentially trigger or accelerate the pathogenesis of AD. RAGE: receptor for advanced glycation end products; LRP: low-density lipoprotein receptor-related protein.