Sporadic Alzheimer?s disease (AD) is an age-dependent neurodegenerative disorder characterized by progressive cognitive dysfunction and memory loss. Pathogenic ?-amyloid (A?) plaques are a hallmark of AD, starting first in the hippocampus before spreading to other parts of the brain. Initial research has primarily focused on how A? aggregates are formed. Despite progress made in understanding progression of AD pathology, fundamental questions remain about what molecular determinants contribute to the onset of AD. Age-dependent genomic changes likely play a role in AD but the molecular players involved have yet to be defined. We show that Chd4, a nucleosome repositioning enzyme, dramatically decreases expression with age in pyramidal neurons of the hippocampus. We propose that Chd4 deletion mimics the epigenomic landscape of old neurons to accelerate the onset of AD pathology. The goal of the proposal is to address the function of Chd4 in the context of AD. We will use tools in single-cell transcriptomics and super-resolution microscopy to determine the molecular changes that occur in pyramidal neurons (Aim1) and the composition of synaptic proteins as well as the integrity of neuronal circuits in the hippocampus (Aim2) after deleting Chd4. We will also determine if A? plaques and memory loss are observed in animals lacking Chd4 (Aim3).
Sporadic Alzheimer?s disease (AD) is the most common cause of dementia in older adults. Epigenetic changes that occur during normal aging contribute to the onset of AD, yet the molecular players involved have not been identified. The goal of this proposal is to understand how the loss of a chromatin remodeling protein, Chd4, may contribute to the onset of AD.
