CHARACTERIZATION OF THE SYNAPTIC PROTEOME IN NON-DEMENTED SUBJECTS WITH ALZHEIMER’S NEUROPATHOLOGY

Some individuals, here refereed to as Non-Demented with Alzheimer’s Neuropathology (NDAN), retain their congitive function despite the presence of amyloid plaques and tau tangles typical of symptomatic Alzheimer’s Disease (AD). In NDAN, unlike AD, toxic amyloid beta oligomers do not localize to the postsynaptic densities (PSDs). Synaptic resistance to amyloid beta in NDAN may thus enable these individuals to remain cognitively intact despite the AD-like pathology. The mechanim(s) responsible for this resistance remains 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 are 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. MicroRNA-149, -4723 and -485 were confirmed to have differential expression in AD and NDAN hippocampi when compared to control. We hypothesize that that global action of selected miRNAs plays a role in resistance to Aβ oligomer binding and toxicity. MicroRNA levels were modulated using mimics and inhibitors in vitro and in vivo. Both experimental systems showed that modulation of selected microRNAs results in reduced Aβ oligomer binding to the cellular surface in vitro and in vivo. 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 retention of cognitive ability.