Epigenetic Modulation of Synaptic Resilience in Alzheimer’s Disease

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Some individuals, here referred to as Non-Demented with Alzheimer’s Neuropathology (NDAN), retain their cognitive function despite the presence of amyloid plaques and tau tangles typical of symptomatic Alzheimer’s Disease (AD). In NDAN, unlike AD, toxic amyloid beta (Aβ) oligomers do not localize to the postsynaptic densities (PSDs). Synaptic resistance to amyloid beta in NDAN may therefore enable these individuals to remain cognitively intact despite the AD-like pathology. The mechanisms responsible for this resistance remain unresolved and understanding such protective biological processes could reveal novel targets for the development of effective treatments for AD. The current work describes the use of a proteomic approach to compare the hippocampal postsynaptic densities of NDAN, AD and healthy age-matched persons to identify protein signatures characteristic for these groups. Subcellular fractionation followed by 2D gel electrophoresis and mass spectrometry were used to analyze the PSDs. Fifteen proteins were identified as the unique proteomic signature of NDAN PSDs, thus setting them apart from control subjects and AD patients. Using Ingenuity Pathway Analysis several microRNAs were identified as potential upstream regulators of the observed changes in the postsynaptic proteome of NDAN. MicroRNA-149, -4723 and -485 were confirmed to have differential expression in AD and NDAN hippocampi when compared to control. When tested in vitro (cellular system) and in vivo (wild-type mice) these microRNAs were capable of reducing Aβ oligomer binding possibly via modulating the key mRNAs. Remarkably, in vivo these protective effects were brain region- and sex-dependent. Taken together, our findings suggest that the unique protein signature at the NDAN PSDs is regulated by the selected microRNAs, while modulation of microRNA levels in vitro and in vivo has an effect on Aβ oligomer binding, further suggesting that a unique regulation of microRNAs in the NDAN subjects could be responsible for protection of synapses from Aβ toxicity, thus contributing to the retention of cognitive ability.

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Alzheimer's Disease, Non-Demented with Alzheimer's Neuropathology, synaptic resistance, microRNA
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