Amyloid-β Peptide Impact on Synaptic Function and Neuroepigenetic Gene Control Reveal New Therapeutic Strategies for Alzheimer’s Disease

Abstract

Amyloid-β (Aβ) 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 Aβ aggregation is either an increase in Aβ production or a decrease in its clearance. Aβ is produced by the sequential activity of β- and γ-secretase on the amyloid precursor protein (APP) and the clearance is mediated by chaperone-mediated mechanisms. The Aβ 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 Aβ levels intact. This hypothesis is strengthened by the absence of positive outcomes and side effects from immunotherapy clinical trials aimed at complete Aβ clearance, and support beneficial physiological roles for native Aβ in cellular function. Aβ has been shown to modulate synaptic transmission, consolidate memory, and protect against excitotoxicity. We discuss the current understanding of beneficial and detrimental roles for Aβ in synaptic function and epigenetic gene control and the future promising prospects of early therapeutic interventions aimed at mediating Aβ induced neuroepigenetic and synaptic dysfunctions to delay AD onset.

The Effects of CSF Neurogranin and APOE ε4 on Cognition and Neuropathology in Mild Cognitive Impairment and Alzheimer’s Disease

“…These findings emphasize the need to understand the physiological and pathological roles of Aβ in order to improve current amyloid based therapeutic strategies (Karisetty et al, 2020). As AD is a multifactorial disease, targeting AD related processes such as tau pathology, synaptic activity, neural epigenetic regulation of AD associated genes, and inflammatory responses may provide alternative treatment strategies (Karisetty et al, 2020). In line with previous studies (De Vos et al, 2015;Hellwig et al, 2015;Portelius et al, 2015;Janelidze et al, 2016;Mattsson et al, 2016;Sanfilippo et al, 2016;Wang, 2019;Xue et al, 2020), we have found that elevated levels of CSF Ng were correlated with T-tau and P-tau in every diagnostic FIGURE 4 | Baseline CSF measures of Ng as predictors of conversion from CN to MCI or AD and MCI to AD.…”

“…Interestingly, some studies have demonstrated the role of Aβ in neuroprotection, synaptic function and memory consolidation ( Lazarevic et al, 2017 ; Finnie and Nader, 2020 ). These beneficial effects are Aβ level and species specificity ( Karisetty et al, 2020 ). Picomolar levels and monomers proved to be beneficial, while high levels and soluble oligomers proved to be harmful ( Karisetty et al, 2020 ).…”

“…These beneficial effects are Aβ level and species specificity ( Karisetty et al, 2020 ). Picomolar levels and monomers proved to be beneficial, while high levels and soluble oligomers proved to be harmful ( Karisetty et al, 2020 ). These findings emphasize the need to understand the physiological and pathological roles of Aβ in order to improve current amyloid based therapeutic strategies ( Karisetty et al, 2020 ).…”

“…Picomolar levels and monomers proved to be beneficial, while high levels and soluble oligomers proved to be harmful ( Karisetty et al, 2020 ). These findings emphasize the need to understand the physiological and pathological roles of Aβ in order to improve current amyloid based therapeutic strategies ( Karisetty et al, 2020 ). As AD is a multifactorial disease, targeting AD related processes such as tau pathology, synaptic activity, neural epigenetic regulation of AD associated genes, and inflammatory responses may provide alternative treatment strategies ( Karisetty et al, 2020 ).…”

Integrative Analysis of Key Candidate Genes and Signaling Pathways in Acute Coronary Syndrome Related to Obstructive Sleep Apnea by bioinformatics

“…The cleaved product of the glycoprotein amyloid precursor protein is AB, which aggregates into AB plaques. According to the amyloid cascade hypothesis, it is these plaques that are responsible for AD pathology 37 . Soluble Ab species can bind to and produce toxicity to various neuronal receptors, leading to cellular oxidative stress and epigenetic-mediated transcription disorders 38 .…”