Transcriptomic dynamics associated with TDP-43 propagation in limbic-predominant age-related TDP-43 encephalopathy neuropathological change

The National Institute on Aging awarded Virginia Polytechnic Institute & State University $762,861 on September 1, 2026, under the Aging Research program (CFDA 93.866) to conduct research on transcriptomic dynamics associated with TDP-43 propagation in limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC).

The project will use quantitative neuropathology and high-resolution spatial transcriptomics to map the distribution of TDP-43, tau, and amyloid-beta pathology and associated neuronal loss in Alzheimer's disease brains with LATE-NC, and will employ spatial sequencing methods to analyze gene expression profiles in brain regions associated with TDP-43 proteinopathy. The research aims to define molecular changes and spatial transcriptomic alterations associated with stage-dependent TDP-43 pathology during early LATE-NC progression in the context of Alzheimer's disease, with emphasis on understanding how TDP-43 pathology originating in the amygdala subsequently involves the hippocampus and other limbic regions.

The period of performance runs from September 1, 2026, through August 31, 2027. Work is performed in Blacksburg, Virginia. This is a Project Grant, classified as an R56 exploratory/developmental award supporting biomedical and behavioral research directed toward understanding aging and age-related diseases.

Abstract

TAR DNA-binding protein 43 (TDP-43) is an essential RNA/DNA-binding protein that regulates RNA processing, alternative splicing, and gene expression. In aging and neurodegenerative disorders, TDP-43 undergoes pathological phosphorylation, ubiquitination, and cytoplasmic aggregation, resulting in neuronal dysfunction and degeneration. In limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (late-NC), TDP-43 pathology is thought to originate in the amygdala and subsequently involve the hippocampus and other limbic regions. However, the spatial molecular changes associated with early late-NC progression remain poorly understood. We hypothesize that stage-dependent TDP-43 pathology is associated with distinct spatial transcriptomic alterations and changes in the local cellular microenvironment during early late-NC progression. To test this hypothesis, we will leverage quantitative neuropathology and high-resolution spatial transcriptomics to define molecular changes associated with regional TDP-43 pathology in high alzheimer's disease neuropathologic change (adnc) brains with late-NC. Our first objective is to map the distribution of pathology (TDP-43, TAU, and amyloid-beta) and neuronal loss in ad brains. In aim 2, we will use spatial sequencing methods to analyze gene expression profiles in brain regions associated with the appearance of TDP-43 proteinopathy. This R56 project will provide new insights into the cellular and molecular mechanisms of late in the context of alzheimer's disease.