Amyloid-Beta Peptide Impact On Synaptic Function And Neuroepigenetic Gene Control Reveal New Therapeutic Strategies For Alzheimer'S Disease

Amyloid-beta (A beta) peptides can form protease-resistant aggregates within and outside of neurons. Accumulation of these aggregates is a hallmark of Alzheimer's disease (AD) neuropathology and contributes to devastating cognitive deficits associated with this disorder. The primary etiological factor for A beta aggregation is either an increase in A beta production or a decrease in its clearance. A beta is produced by the sequential activity of beta- and gamma-secretase on the amyloid precursor protein (APP) and the clearance is mediated by chaperone-mediated mechanisms. The A beta aggregates vary from soluble monomers and oligomers to insoluble senile plaques. While excess intraneuronal oligomers can transduce neurotoxic signals into neurons causing cellular defects like oxidative stress and neuroepigenetic mediated transcriptional dysregulation, extracellular senile plaques cause neurodegeneration by impairing neural membrane permeabilization and cell signaling pathways. Paradoxically, senile plaque formation is hypothesized to be an adaptive mechanism to sequester excess toxic soluble oligomers while leaving native functional A beta levels intact. This hypothesis is strengthened by the absence of positive outcomes and side effects from immunotherapy clinical trials aimed at complete A beta clearance, and support beneficial physiological roles for native A beta in cellular function. A beta has been shown to modulate synaptic transmission, consolidate memory, and protect against excitotoxicity. We discuss the current understanding of beneficial and detrimental roles for A beta in synaptic function and epigenetic gene control and the future promising prospects of early therapeutic interventions aimed at mediating A beta induced neuroepigenetic and synaptic dysfunctions to delay AD onset.