A Multifactorial Mechanism for Alzheimer's Disease

Va Western New York Healthcare System, Buffalo NY

Investigators

Abstract

Project Summary There is a dramatic increase in the prevalence of dementia among veterans, because of the aging of the veteran population and a high prevalence of dementia risk factors among veterans. Alzheimer’s disease (AD) is the most predominant neurodegenerative disorder linked to dementia. This project aims to identify key molecules and mechanisms that link pathological abnormalities to cognitive impairment in AD. Our transcriptomic analysis of large-scale postmortem AD human prefrontal cortex (PFC) data has revealed that the upregulated genes are prominently enriched in the complement pathway, and our epigenomic analysis has identified ADNP (Activity-Dependent Neuroprotective Protein), a chromatin regulator strongly linked to intellectual disability, as the top-ranking transcription factor regulating the elevated complement genes in AD. Our preliminary data have shown that ADNP and its partner HP1 (Heterochromatin protein 1) are significantly diminished in postmortem AD human PFC. ADNP knockdown in mouse PFC induces genetic dysregulation, synaptic dysfunction, microglia activation and behavioral abnormalities reminiscent of a familial AD mouse model, 5xFAD. Thus, we hypothesize that the ADNP-mediated chromatin dysregulation leads to complement activation due to the disrupted gene repression, which triggers microglia activation and synapse loss by phagocytosis, resulting in cognitive impairment. To test this, multidisciplinary approaches will be used to address 3 specific aims. Aim 1. To investigate the role of ADNP in the elevation of complement genes in AD. Aim 2. To investigate the impact of ADNP and complement system on synaptic dysfunction and cognitive deficits in AD mouse models. Aim 3. To investigate the therapeutic potential of manipulating ADNP and complement system in human iPSC-derived neuronal cultures from AD patients. Results gained from this study will reveal novel mechanisms on AD pathophysiology, and provide great promise for the discovery of mechanism-based therapies to treat AD.