Proteolytic Degradation of Amyloid  -Protein

Abstract

The amyloid b-protein (Ab) is subject to proteolytic degradation by a diverse array of peptidases and proteinases, known collectively as Ab-degrading proteases (AbDPs). A growing number of AbDPs have been identified, which, under physiological and/or pathophysiological conditions, contribute significantly to the determination of endogenous cerebral Ab levels. Despite more than a decade of investigation, the complete set of AbDPs remains to be established, and our understanding of even well-established AbDPs is incomplete. Nevertheless, the study of known AbDPs has contributed importantly to our understanding of the molecular pathogenesis of Alzheimer disease (AD) and has inspired the development of several novel therapeutic approaches to the regulation of cerebral Ab levels. In this article, we discuss the general features of Ab degradation and introduce the best-characterized AbDPs, focusing on their diverse properties and the numerous conceptual insights that have emerged from the study of each.

Impaired synaptic function is linked to cognition in Parkinson's disease

“…Alternatively, defective presynaptic proteolysis and lysosomal degradation could affect both A β and α ‐synuclein metabolism 7, 8, 46. In either case, postsynaptic spines would be affected secondarily, likely leading to the observed reduced levels of neurogranin.…”

“…Intracellular metabolism of these proteins is performed by overlapping sets of enzymes and subcellular compartments 7, 8, 9, 10. Presynaptic activity and endocytosis influence release of amyloid‐ β (A β ) species to the interstitial fluid 11.…”

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

“…There are two major pathways by which Ab is cleared from the brain: (1) receptor-mediated clearance by cells in brain parenchyma (microglia, astrocytes, neurons), along the interstitial fluid (ISF) drainage pathway or through the BBB and (2) through endopeptidase-mediated proteolytic degradation (see Saido and Leissring 2011 for details on proteolytic degradation of Ab). Receptor-mediated clearance of Ab in the brain is at least partially mediated by the apoE receptors LRP1, LDLR, and VLDLR, which are widely expressed in neurons, astrocytes, and microglia of brain parenchyma, as well as in endothelial cells, astrocytes, and smooth muscle cells at the BBB and cerebral arteries.…”

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

“…One example is the multidrug transporter P-glycoprotein (Pgp). Evidence supporting this role for Pgp includes: (1) observations of Pgp-dependent efflux of Ab in vitro, 59,60 (2) an inverse correlation of Ab deposition and microvascular Pgp expression in human brain tissue, 61 (3) decreased Ab efflux and enhanced Ab deposition in mice that lack Pgp, 62 (4) impaired microvascular Pgp function in a transgenic AD mouse model that is restored by pharmacologic intervention shows corresponding improvement in Ab efflux and reduced Ab deposition, 62,63 and (5) showing Pgp dysfunction in human AD using clinical PET imaging studies. 64 Because of its luminal location, 65 it has been proposed that Pgp facilitates the extrusion of Ab from the endothelial cell into the bloodstream after Ab has been internalized from brain interstitial fluid (ISF) by LRP-1.…”

“…In the remainder of AD cases, it is thought that Ab deposition results from deficient clearance. 2 Multiple routes of clearance have been elucidated for Ab, including enzymatic degradation, 3 bulk flow of cerebrospinal fluid (CSF), 4 and transport across central nervous system (CNS)-blood barriers. 5 These pathways are illustrated in Figure 1, and will be described in detail in later sections.…”