Molecular Mechanisms Underlying Behavioral and Psychological Symptoms in Alzheimers Disease

Project: Research project

Project Details

Description

In addition to memory loss and other cognitive deficits, over 90% of Alzheimer’s disease (AD) patients suffer from behavioral and psychological symptoms of dementia (BPSD), including agitation, aggression, disinhibition, apathy, depression, and delusions/hallucinations. BPSD can present at almost any stage of AD, and in some patients, symptoms can even appear before dementia develops. BPSD severity increases significantly with disease progression, affecting quality of life for both patients and their caregivers, and is the main reason for institutionalization. However, the mechanisms underlying BPSD are not known, and there is no targeted or widely effective treatment strategy available. Though BPSD presents differently for each patient, the presence of certain symptoms in a patient makes the co-occurrence of other symptoms more likely. As an ongoing collaboration with Rush University Alzheimer’s Disease Center, we have established a novel approach to cluster symptoms in AD patients into four BPSD domains (affective, hyperactivity/disinhibition, psychosis and apathy). Based on these domains, we conducted the RNA-seq and found altered gene expression profiles associated with BPSD domains. This evidence supports the notion that the interaction of distinct molecular pathways is associated with different BPSD domains in AD. Thus, we hypothesize that individual BPSD domains in AD are due to definable perturbations in molecular pathways and these pathways could be analogized in AD mouse models, allowing for causal investigation of specific pathway alterations and resulting behavior. We will test this hypothesis through postmortem analysis in human subjects and preclinical disease modeling. For the human study, 1) we will expand on our behavioral analyses by increasing the pre-mortem clinical assessments and defining BPSD trends over time in AD patients. 2) Within each behavioral domain, we will employ RNA-seq to investigate gene expression changes in different brain sub-regions that are unique to each BPSD domain. Additionally, gene expression by domain will be compared between normal, MCI and AD subjects. 3) We will identify which pathways are the most affected in each specific domain using bioinformatics and biochemical analyses. For the pre-clinical mouse model study, 1) we will establish BPSD-like symptom domains in APP/PS1 and Tg2576 mice and characterize how these symptoms evolve during AD progression and how similar they are to the human condition. 2) We will verify the most promising molecular candidates from our RNA-seq findings in AD/BPSD models. 3) We will determine if altering these pathways using virally mediated genetic manipulations (AAV9/CRISPR-Cas9) leads to changes in BPSD-like behavior in our mouse models. Overall, this project will establish a translational pipeline from associating BPSD domains with molecular alterations in human AD patients to demonstrating that manipulation of these pathways causes BPSD-like behaviors in transgenic AD mice. These data-driven approaches will lead to a better understanding of the molecular mechanisms of BPSD in AD and potentially identify novel targets for future therapeutic approaches.
StatusActive
Effective start/end date9/30/185/31/23

Funding

  • National Institute of Aging (5R01AG062249-02)

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