Exp Neurobiol.  2022 Apr;31(2):65-88. 10.5607/en22004.

Physiological Roles of Monomeric Amyloid-β and Implications for Alzheimer’s Disease Therapeutics

• Jeong H
• Shin H
• Hong S
• Kim Y

• KMID: 2530365
• DOI: http://doi.org/10.5607/en22004

Abstract

Alzheimer’s disease (AD) progressively inflicts impairment of synaptic functions with notable deposition of amyloid-β (Aβ) as senile plaques within the extracellular space of the brain. Accordingly, therapeutic directions for AD have focused on clearing Aβ plaques or preventing amyloidogenesis based on the amyloid cascade hypothesis. However, the emerging evidence suggests that Aβ serves biological roles, which include suppressing microbial infections, regulating synaptic plasticity, promoting recovery after brain injury, sealing leaks in the blood-brain barrier, and possibly inhibiting the proliferation of cancer cells. More importantly, these functions were found in in vitro and in vivo investigations in a hormetic manner, that is to be neuroprotective at low concentrations and pathological at high concentrations. We herein summarize the physiological roles of monomeric Aβ and current Aβ-directed therapies in clinical trials. Based on the evidence, we propose that novel therapeutics targeting Aβ should selectively target Aβ in neurotoxic forms such as oligomers while retaining monomeric Aβ in order to preserve the physiological functions of Aβ monomers.

Keyword

Alzheimer’s disease; Amyloid beta-peptides; Amyloidosis; Neurodegenerative diseases; Therapeutics