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

Alzheimer's disease (AD) progressively inflicts impairment of synaptic functions with notable deposition of amyloid-beta (A beta) as senile plaques within the extracellular space of the brain. Accordingly, therapeutic directions for AD have focused on clearing A beta plaques or preventing amyloidogenesis based on the amyloid cascade hypothesis. However, the emerging evidence suggests that A beta 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 A beta and current A beta-directed therapies in clinical trials. Based on the evidence, we propose that novel therapeutics targeting A beta should selectively target A beta in neurotoxic forms such as oligomers while retaining monomeric A beta in order to preserve the physiological functions of A beta monomers.

Automated summary

Alzheimer's disease (AD) has been mainly focused on clearing A beta plaques or preventing amyloidogenesis. However, recent evidence has shown that A beta has biological functions, such as suppressing microbial infections and regulating synaptic plasticity. Therefore, novel therapeutics targeting A beta should selectively target neurotoxic forms while preserving the physiological functions of A beta monomers.