EPIGENETIC REGULATION OF NEUROGENESIS IN NON-DEMENTED HUMANS WITH ALZHEIMER’S DISEASE NEUROPATHOLOGY

This project was designed to investigate the role of neurogenesis and its epigenetic regulation by microRNA in the preservation of cognition against Alzheimer’s disease. This was accomplished by comparing by immunohistochemistry the capacity for neurogenesis in the subgranular zone of the hippocampus in 4 distinct populations of human subject’s tissue representing the full disease, intermediate cognitive decline, healthy controls, and a poorly characterized group who have all of the histopathological hallmarks of the full disease but are cognitively normal. To investigate the microRNAs of interest in the correct context, as microRNA expression can vary significantly by region, the granular cell layer and the subgranular zone were microdissected from the same subjects investigated for neurogenesis. This was paired with an investigation of neurogenesis and the same microRNAs in a mouse model of metabolic syndrome, as metabolic syndrome is one of the major risk factors for the development of AD. These animals had previously demonstrated memory deficits when raised on a high-fat diet. Cognitively impaired human subjects showed relative decreases in neurogenic capacity. Meanwhile those with histopathology but without cognitive decline demonstrated a significantly enhanced capacity for neurogenesis, in spite of the usually deleterious accumulations associated with the disease. These individuals also demonstrated a significant decrease of expression of all the microRNAs investigated; a trend that clearly opposed the direction of regulation seen in the mildly and significantly impaired individuals. In the animal model of metabolic disorder, no difference in neurogenesis was discovered but the direction of the microRNA expression was increased, consistent with that seen the cognitively impaired humans. It is reasonable to conclude that preserved or expanded neurogenesis is one of the factors that contributes to the preserved cognitive capabilities in the non-demented humans with Alzheimer’s Disease neuropathology, and that this change is in part due to deregulation of the miRNA activity in the neurogenic niche. Further, the investigated mouse model appears promising as an atypical model for Alzheimer’s for its tendency toward recapitulating uncommon but features of the neurocognitive disease.