Are amyloid‐degrading enzymes viable therapeutic targets in Alzheimer’s disease?

Abstract

J. Neurochem. (2012) 120 (Suppl. 1), 167–185. Abstract The amyloid cascade hypothesis of Alzheimer’s disease envisages that the initial elevation of amyloid β‐peptide (Aβ) levels, especially of Aβ1‐42, is the primary trigger for the neuronal cell death specific to onset of Alzheimer’s disease. There is now substantial evidence that brain amyloid levels are manipulable because of a dynamic equilibrium between their synthesis from the amyloid precursor protein and their removal by amyloid‐degrading enzymes (ADEs) providing a potential therapeutic strategy. Since the initial reports over a decade ago that two zinc metallopeptidases, insulin‐degrading enzyme and neprilysin (NEP), contributed to amyloid degradation in the brain, there is now an embarras de richesses in relation to this category of enzymes, which currently number almost 20. These now include serine and cysteine proteinases, as well as numerous zinc peptidases. The experimental validation for each of these enzymes, and which to target, varies enormously but up‐regulation of several of them individually in mouse models of Alzheimer’s disease has proved effective in amyloid and plaque clearance, as well as cognitive enhancement. The relative status of each of these enzymes will be critically evaluated. NEP and its homologues, as well as insulin‐degrading enzyme, remain as principal ADEs and recently discovered mechanisms of epigenetic regulation of NEP expression potentially open new avenues in manipulation of AD‐related genes, including ADEs.

Regulation of β cleavage of amyloid precursor protein

“…A is physiologically derived from  and  cleavage of APP and degraded by a number of enzymes [79] , although the normal function of A remains still not well understood. A accumulates when the balance between its production and clearance is broken, and FAD-linked mutations of APP and presenilins could enhance A production and lead to early onset AD, suggesting that A overproduction is able to induce the disease onset.…”

Molecular mechanisms of reversing neural degeneration by retinoic acid, a major derivative of vitamin A

“…This phenomenon will be discussed in detail under the section on suppression of amyloid beta by retinoic acid (4.3). Glutathione suppression is widely seen in degeneration of dopaminergic neurons in PD (Nalivaeva et al, 2012a) and SOD suppression is a common phenomenon in AD (Lee et al, 2009 ). Therefore, retinoic acid could be used as a promising therapeutic drug for most abundant neurodegenerative diseases.…”

“…Amyloid β is a small peptide which has a direct connection with neuro degeneration and it is a well-studied oligomer in neurodegenerative diseases (Nalivaeva et al, 2012a;Miners et al, 2011;Nalivaeva et al, 2008;Nalivaeva et al, 2012b;Koryakina et al, 2009;Morishima et al, 2001) even though few good functions of Aβ have been identified such as synaptic transmission (Turner et al, 2003). Elevated amounts of Aβ can result in pathogenic situations (Nalivaeva et al, 2012b;Koryakina et al, 2009;Morishima et al, 2001).…”

“…Understanding molecular mechanisms coupled with the production of Aβ and Aβ related pathogenesis is really important in deciphering neurodegenerative diseases such as AD. Over the past decade, the major concern for therapeutic drug target has been the reduction of Aβ levels in neurons (Miners et al, 2011;Nalivaeva et al, 2008;Nalivaeva et al, 2012b). The Aβ liberation from the Aβ precursor protein (APP) is tightly regulated as excess Aβ accumulation causes adverse cellular effects, subsequently activating PCD (Nalivaeva et al, 2012a).…”

Estrogen and Brain Protection

“…This may be due to the mutations of presenelin genes, which provoke the overproduction of Amyloid from amyloid precursor protein (Hardy, 2004). In late-onset Alzheimer's disease, which constitutes more than 90% of the disease, the excess accumulation of Amyloid has been associated with abnormal Amyloid degrading proteases (Nalivaeva et al, 2008). Women are more likely to develop Alzheimer's disease after adjusting for age (Andersen et al, 1999).…”