Major barriers impede the translation of basic research findings from preclinical animal models of Alzheimer's disease (AD) into the discovery of methods for early detection of AD onset and the treatment of memory dysfunction. We hypothesize that early dysfunction of memory will be observable as dysfunction of hippocampal trisynaptic circuit dynamics (TCDs) that are specifically associated with spatial memory. The individual firing patterns of CA3 & CA1 pyramidal cells (or ?place cells?) within the trisynaptic circuit can be measured while acquisition, encoding, recall, and reconsolidation of spatial representations occurs. Our recent in vivo studies of aged animals, a model for amnestic mild cognitive impairment, have revealed age and novelty specific effects on CA3 & CA1 place cell dynamics that are rapidly reversed by acute administration of levetiracetam + valproic acid (Robitsek 2015). We also hypothesize that changes in properties of single neurons within the trisynaptic circuit will be an early signature for future behavioral impairment and for identifying genome responses that may be most relevant to AD during the prodromal phase. In this multidisciplinary application, we propose to use the novel TgF344-AD rat model (expressing mutant human amyloid precursor protein (APPsw) and presenilin 1 (PS1?E9)) to identify hippocampal TCDs that change during development of AD-associated memory dysfunction and to interrogate their underlying transcriptome and methylome. Prodromal changes in neural activity appear to play a role in the progression of neuropathological changes observed in AD by promoting the release of tau and the formation of neurofibrillary tangles. Accordingly, plasma tau levels are associated with cognitive decline and conversion of mild cognitive impairment into dementia. Less is known, however, about the cell specific response of the genome during the onset and course of AD progression that may factor significantly into disease etiology and resilience, nor the composition of the transcriptome of individual cells that respond dynamically to the onset and growing burden of inflammation. As a first step to fill this gap in knowledge, we propose the following two Aims: 1) To determine the temporal window for altered neural network activity in TgF344-AD rats that anticipates the age related progressive deterioration of spatial memory (in vivo electrophysiology); and 2) To determine the transcriptome of unique cell types in the TgF344-AD hippocampus (single cell RNA-sequencing (scRNA-seq) using a within-subjects design (Aim 1)) and the state of the TgF344-AD hippocampal genome as determined in parallel molecular studies (bulk RNA-seq and Methyl-seq). The proposed research has the potential to detect prodromal signatures of genomic events that underlie the onset of memory decline, uncovering relevant molecular determinants that may enable interventions to enhance memory and, conceivably, slow disease progression and human suffering.
Progress in Alzheimer's Disease has been plagued by a lack of concordance between discoveries coming from preclinical animal models of later stage disease and the development of effective treatments for human patients. In response to these failures, investigators are now using animal models to study the early stage of AD (ie prodromal) which is characterized by mild cognitive impairment and may be more amenable to drug treatment. Our proposed research takes this one- step further by using early changes in the functional activity of cells in conserved local memory circuits as a marker of disease ?onset? to discover the disturbed transcriptomes of vulnerable hippocampal cells and to provide new insights into disease mechanism and future drug development.
