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

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.

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

Fig. 1

The physiological roles of amyloid-β (Aβ). (a) Aβ has an antimicrobial property: Aβ induces agglutination and inhibits the adhesion of pathogens to host cells. (b) Aβ regulates synaptic functions: picomolar concentrations of Aβ42 increase the concentration of acetylcholine (ACh), by acting as an allosteric enhancer of choline acetyltransferase (ChAT), causing an influx of Ca²⁺ through α7-nicotinic acetylcholine receptors (α7-nAChRs), which eventually lead to an increase in long-term potentiation (LTP). (c) Aβ promotes recovery from brain injury: during the recovery of traumatic brain injury (TBI), the levels of Aβ elevate, hinting a protective role of Aβ against brain injury. (d) Aβ serves as a sealant of blood-brain barrier (BBB) leakages. (e) Monomeric forms of Aβ dose-dependently promote angiogenesis. (f) Aβ suppresses tumor growth by promoting apoptosis.