. Alzheimer's Disease (AD) is increasingly conceived as a disorder of the synapse. Yet, despite decades of investigations, the relationship between synaptic pathology and well established ?-amyloid and tau pathology is not well understood. Emerging evidence strongly indicates that the extracellular matrix (ECM) may represent a critical element in this relationship, largely neglected thus far. The ECM, a molecular network representing 20% of the brain volume, plays a key role in neuroprotection, synaptic stabilization and plasticity, and interacts with ?-amyloid and tau. It organizes into aggregates such as perineuronal nets (PNNs), organized ECM perisynaptic structures enveloping neuronal populations and regulating synaptic stabilization and neuroprotection. Based on preliminary data showing a dramatic loss of PNN integrity and significant changes of ECM composition in AD, we put forth that the ECM may represent a key element of pathophysiological mechanisms involving synaptic, ?-amyloid and tau pathology in AD. However, little is known about expression and function of ECM and their relevance in Alzheimer Disease. Our central hypotheses for this supplemental application are that ECM abnormalities, mediated by altered expression of the transcription factor OTX2 and matrix metalloproteinases (MMPs), may represent a key link between synaptic disruption and ?-amyloid and tau pathology in AD, potentially contributing to cognitive decline in this disorder. We will test our hypotheses through two specific aims:
Specific Aim 1 will expand our robust preliminary dataset on OTX2 and extracellular matrix regulation probing the dysregulation of OTX2, MMPs and ECM in AD. Specifically, this aim will test the hypothesis that a dysregulation of OTX2 and MMPs in the choroid plexus is part of an upstream signaling cascade responsible for a disintegration of PNN/ECM and subsequent synaptic loss in the brain parenchyma, specifically the amygdala.
Specific Aim 2 will use machine-learning technologies to extract symptom dimensions based on the NIH RDoc definitions from tissue donors' records including a model of cognition that has been validated against neuropsychiatric testing. This process will be scaled up to develop a rich multi-dimensional phenotypic index and integrated with results from studies in Specific Aim 1. The large subject cohort to be used for these studies will allow us to further develop and validate this approach.
. The proposed research is highly relevant to public health because the discovery of molecular mechanisms leading to cognitive decline and dementia in post-mortem human brain tissue of aged individuals, subjects with Alzheimer's Disease (AD) and healthy donors will provide crucial insights into the pathophysiology of AD. This will provide conceptually new ways to think about the pathophysiology of this disorder and lead to novel preventive and therapeutic strategies. Thus, the project is relevant to the NIMH/NIA's mission in that it seeks fundamental knowledge about the nature of mental disorders, and aging in particular as well as the application of that knowledge to cure and prevent mental health and aging-related disorders.
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