Targeting amyloid clearance in Alzheimer's disease as a therapeutic strategy

Abstract

Targeting the amyloid‐β (Aβ) peptide cascade has been at the heart of therapeutic developments in Alzheimer's disease (AD) research for more than 25 years, yet no successful drugs have reached the marketplace based on this hypothesis. Nevertheless, the genetic and other evidence remains strong, if not overwhelming, that Aβ is central to the disease process. Most attention has focused on the biosynthesis of Aβ from its precursor protein through the successive actions of the β‐ and γ‐secretases leading to the development of inhibitors of these membrane proteases. However, the levels of Aβ are maintained through a balance of its biosynthesis and clearance, which occurs both through further proteolysis by a family of amyloid‐degrading enzymes (ADEs) and by a variety of transport processes. The development of late‐onset AD appears to arise from a failure of these clearance mechanisms rather than by overproduction of the peptide. This review focuses on the nature of these clearance mechanisms, particularly the various proteases known to be involved, and their regulation and potential as therapeutic targets in AD drug development. The majority of the ADEs are zinc metalloproteases [e.g., the neprilysin (NEP) family, insulin‐degrading enzyme, and angiotensin converting enzymes (ACE)]. Strategies for up‐regulating the expression and activity of these enzymes, such as genetic, epigenetic, stem cell technology, and other pharmacological approaches, will be highlighted. Modifiable physiological mechanisms affecting the efficiency of Aβ clearance, including brain perfusion, obesity, diabetes, and sleep, will also be outlined. These new insights provide optimism for future therapeutic developments in AD research. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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“…Release of APOE and cytokines [115] Improve behavioral symptoms [116] Not clarified for the neuroprotective effect experimental pro-amyloidogenic properties. This is probably consistent with the much lower efficiency of hydrolysis of Aβ by ACE compared to other Aβ degrading enzymes, such as neprilysin, endothelin-converting enzyme, and insulindegrading enzyme (reviewed in [48]). ACE inhibitors might also act by other pathways which are beneficial for cognition, as shown in some preclinical studies above.…”

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“…Modi iable physiological mechanisms affecting the ef iciency of Aβ clearance, including brain perfusion, obesity, diabetes, and sleep, will also be outlined. These new insights provide optimism for future therapeutic developments in AD research [26].…”

“…Two such monoclonal antibodies were initially developed in 2014 to remove these plaques from the brains of people with AD38,39. Neither medication improved cognitive scores in patients with mild-to-moderate disease (MMSE [16][17][18][19][20][21][22][23][24][25][26], leading researchers to conclude that these medications may show bene it only when administered in the early stages of MCI and mild dementia. However, a new study regarding the effect of this class of medication in patients with few to no symptoms (MMSE 20-26) but a positive amyloid PET imaging result also failed to show a signi icant difference in cognitive outcomes between the study group and asymptomatic controls40.…”

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“…Despite a previously predominant therapeutic focus on modulators of the APP processing, Nalivaeva and Turner () highlight that Aβ levels in the brain are not only regulated through production but also clearance. This clearance is largely considered to occur through proteolysis by key amyloid degrading enzymes and transport processes requiring proteins such as transthyretin.…”