Selected microRNAs Increase Synaptic Resilience to the Damaging Binding of the Alzheimer’s Disease Amyloid Beta Oligomers

Abstract

Alzheimer's disease (AD) is marked by synaptic loss (at early stages) and neuronal death (at late stages). Amyloid beta (Aβ) and tau oligomers can target and disrupt synapses thus driving cognitive decay. Non-demented individuals with Alzheimer's neuropathology (NDAN) are capable of withstanding Aβ and tau toxicity, thus remaining cognitively intact despite presence of AD neuropathology. Understanding the involved mechanism(s) would lead to development of novel effective therapeutic strategies aimed at promoting synaptic resilience to amyloid toxicity. NDAN have a unique hippocampal post-synaptic proteome when compared with AD and control individuals. Potential upstream modulators of such unique proteomic profile are miRNA-485, miRNA-4723 and miRNA-149, which we found differentially expressed in AD and NDAN vs. control. We thus hypothesized that these miRNAs play an important role in promoting either synaptic resistance or sensitization to Aβ oligomer binding. Using an in vivo mouse model, we found that administration of these miRNAs affected key synaptic genes and significantly decreased Aβ binding to the synapses. Our findings suggest that miRNA regulation and homeostasis are crucial for Aβ interaction with synaptic terminals and support that a unique miRNA regulation could be driving synaptic resistance to Aβ toxicity in NDAN, thus contributing to their preserved cognitive abilities.

Roles and Mechanisms of Gut Microbiota in Patients With Alzheimer’s Disease

“…Numerous studies in recent decades have focused on elucidating the etiopathology of AD, but its pathogenesis remains unclear, and no therapeutic strategy is available to cure this disease. Various molecular, biochemical, and cellular abnormalities such as cell loss, impaired energy metabolism, increased activation of signaling pathways, amyloid-β (Aβ) deposits, mitochondrial dysfunction, chronic oxidative stress, impaired energy metabolism, and DNA damage are involved in the pathogenesis of AD (Guo et al, 2020;Zhang Y. X. et al, 2020;Zolochevska and Taglialatela, 2020;Ashford et al, 2021). The neuropathological hallmarks of AD include the formation of senile plaques and neurofibrillary tangles in specific brain regions that lead to synaptic loss and neuronal death (Khan and Hegde, 2020;Mattsson-Carlgren et al, 2020;Konijnenberg et al, 2021).…”

Personalizing the Care and Treatment of Alzheimer’s Disease: An Overview

“… 174 A similar effect was achieved with miR-188-5p oligonucleotide transfection in 5XFAD mouse model of AD. 175 Zolochevska et al 176 used in vivo mouse model and intracerebroventricular injections to demonstrate that miR-149, miR-485 and miR-4723 could prevent Aβ oligomer binding to the synapses. The miR-200b and miR-200c mimics were also able to prevent Aβ-derived toxicity in mice.…”

Current Status of microRNA-Based Therapeutic Approaches in Neurodegenerative Disorders

“…Apart from this, hippocampal injections of miR-34c inhibitors restored SIRT1 levels, a protein that contributes to memory impairment when absent [ 49 ]; intranasal delivery of the aforementioned miRNA antagomir reversed the deterioration of dendritic spines caused by β-Amyloid (Aβ) protein [ 50 ]; this was equally achieved after miR-188-5p oligonucleotide transfection into primary hippocampal neurons from 5XFAD mice [ 51 ]. Recently, Zolochevska et al [ 52 ] explored the impact of three different miRNAs (miR-149, miR-485 and miR-4723) in resilience against Aβ oligomers, which may produce synaptic dysfunction after interacting with the synapses; in vivo experiments where miRNAs were introduced via ICV injection in both male and female mice suggested that all the selected microRNAs could prevent Aβ oligomer binding. Interestingly, it was detected that target genes and RNA regulation are sex-specific.…”