Experimental approaches for altering the expression of Abeta‐degrading enzymes

Abstract

Cerebral clearance of amyloid β‐protein (Aβ) is decreased in early‐onset and late‐onset Alzheimer's disease (AD). Aβ is cleared from the brain by enzymatic degradation and by transport out of the brain. More than 20 Aβ‐degrading enzymes have been described. Increasing the degradation of Aβ offers an opportunity to decrease brain Aβ levels in AD patients. This review discusses the direct and indirect approaches which have been used in experimental systems to alter the expression and/or activity of Aβ‐degrading enzymes. Also discussed are the enzymes' regulatory mechanisms, the conformations of Aβ they degrade, where in the scheme of Aβ production, extracellular release, cellular uptake, and intracellular degradation they exert their activities, and changes in their expression and/or activity in AD and its animal models. Most of the experimental approaches require further confirmation. Based upon each enzyme's effects on Aβ (some of the enzymes also possess β‐secretase activity and may therefore promote Aβ production), its direction of change in AD and/or its animal models, and the Aβ conformation(s) it degrades, investigating the effects of increasing the expression of neprilysin in AD patients would be of particular interest. Increasing the expression of insulin‐degrading enzyme, endothelin‐converting enzyme‐1, endothelin‐converting enzyme‐2, tissue plasminogen activator, angiotensin‐converting enzyme, and presequence peptidase would also be of interest. Increasing matrix metalloproteinase‐2, matrix metalloproteinase‐9, cathepsin‐B, and cathepsin‐D expression would be problematic because of possible damage by the metalloproteinases to the blood brain barrier and the cathepsins' β‐secretase activity. Many interventions which increase the enzymatic degradation of Aβ have been shown to decrease AD‐type pathology in experimental models. If a safe approach can be found to increase the expression or activity of selected Aβ‐degrading enzymes in human subjects, then the possibility that this approach could slow the AD progression should be examined in clinical trials.

Brain Region-Specific Differences in Amyloid-β Plaque Composition in 5XFAD Mice

“…While, depending on the underlying mutations in APP and PSEN genes, increased Aβ levels in FAD cases may be associated with increased Aβ production, a disequilibrium between production and clearance mechanisms is regarded as a main contributor to Aβ accumulation in sporadic AD cases [28]. A variety of candidate proteases involved in brain Aβ degradation, such as neprilysin (NEP), insulin-degrading enzyme (IDE) or endothelin-converting enzyme (ECE) have been described in recent years [29]. In addition, the transport of soluble Aβ across the blood-brain barrier via Aβ transporters such as low density lipoprotein receptor-related protein 1 (LRP1) has been implicated in Aβ homeostasis [30].…”

Antibody-Mediated Clearance of Brain Amyloid-β: Mechanisms of Action, Effects of Natural and Monoclonal Anti-Aβ Antibodies, and Downstream Effects

“…NSAIDs, pioglitazone, rosiglitazone, and curcumin are agents which have been suggested to promote glial cell M2-type activation [322][323][324][325][326]. Increasing the expression and/or activity of microglial enzymes which degrade A␤ such as neprilysin, insulin-degrading enzyme, tissue plasminogen activator, cathepsin B, and matrix metalloproteinases [327] might also increase antibody-facilitated clearance of A␤ by microglia. In addition, enhancing the other mechanisms by which antibodies promote cerebral clearance of A␤ might enhance the ability of monoclonal antibodies to lower brain A␤.…”

Enhancing of cerebral Abeta clearance by modulation of ABC transporter expression: a review of experimental approaches

“…The literature includes descriptions of many experimental approaches for reducing brain levels of Aβ. Experimental approaches for increasing proteolytic degradation and antibody-mediated clearance of Aβ were recently reviewed by this author ( Loeffler, 2023a , b ). Additional mechanisms through which Aβ is cleared from the brain include its efflux across the blood brain barrier (BBB) ( Qosa et al, 2014 ; Versele et al, 2022 ) and blood cerebrospinal fluid barrier (BCSFB) ( Crossgrove et al, 2005 ; Shen et al, 2020 ), glymphatic drainage ( Iliff et al, 2012 ; Li et al, 2022 ), and perivascular drainage ( Bell et al, 2007 ; Zhang et al, 2021 ).…”