Novel Pathogenetic Mechanism for Hippocampal Sclerosis, a Common Alzheimers Mimic

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Description

Hippocampal sclerosis of aging (HS-Aging) is a major pathologic substrate of non-Alzheimer¡¦s disease (AD) dementia. HS-Aging affects ~20% of elderly persons and causes substantial cognitive impairment. However, in the clinical setting, HS-Aging is generally misdiagnosed as AD, and there currently is no way of diagnosing HS-Aging during life. Studying HS-Aging, we discovered a novel mechanism of neurodegeneration that may provide a much-needed new biomarker and a therapeutic target to improve the care of millions at risk for dementia: HS-Aging is associated with perturbation of thyroid hormone (TH) levels in the brain. Extensive preliminary data support this hypothesis and many prior studies have linked TH dysregulation with dementia. However, critical questions must be addressed. The following are testable hypotheses that emerge from preliminary studies: a) Human hippocampal pathology is associated with clinical TH status; b) CSF TH levels provide a novel biomarker for HS-Aging in the clinical setting; c) Specific gene variants influence expression of ABCC9 and SLCO1C1 genes, causing altered brain TH levels contributing to HS-Aging pathogenetically; and d) Orally administered drugs influence a brain gene expression cascade that is directly relevant to HS-Aging pathogenesis. To test these hypotheses, we propose a research program with the following Specific Aims: Specific Aim 1: Define how human hippocampal pathologies are associated with clinical TH status. We hypothesize that human HS-Aging and TDP-43 pathologies are associated with brain TH perturbation. We will analyze a convenience sample of 205 cases and various dementia controls, with rigorous and cutting-edge digital neuropathologic data, correlated with clinical TH status. Specific Aim 2: Evaluate TH (triiodothyronine, or T3) in CSF as a human biomarker of HS-Aging/SNAP. We will evaluate human CSF TH levels with direct correlation with various subtypes of pathology. We also will test TH in clinical CSF from lumbar punctures, correlated with established AD-related biomarkers (Abeta and tau) and HS-Aging SNPs, with the goal of developing a novel method to diagnose HS-Aging in living persons. We have obtained CSF from 104 autopsied individuals and 195 clinical CSF samples to accomplish this Aim. Specific Aim 3: Define gene expression changes relevant to TH and HS-Aging. Preliminary data indicate a novel gene regulatory mechanism and therapeutic target. We will analyze human genomics databases to elucidate the single nucleotide polymorphisms (SNPs) that have been linked to both HS-Aging risk and also to variability in ABCC9 and SLCO1C1 expression in human brain. We will test human cells (cultured human hESC astrocytes and lymphoblastoid cells related to people with known genotypes and pathology) to determine the potential for manipulating the levels of ABCC9, of thyroid hormone transporter, of SLCO1C1, and of thyroid hormone-regulated genes. Finally, in mice in vivo, we will test how the genes respond to thyroid hormone and to ABCC9-regulating drug glimepiride (relative to control and metformin).
StatusActive
Effective start/end date7/15/173/31/23

Funding

  • National Institute on Aging: $2,213,747.00

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