Dysfunctional lipid metabolism in Alzheimer's Disease

National Institute On Aging

Investigators

Linked publications & trials

Abstract

Alzheimer's Disease (AD) is a major source of suffering, disability and societal costs that currently lacks effective treatment options. Variants in lipid metabolism genes are among the strongest risk factors for late-onset AD. However, the specific mediators and mechanisms linking dysfunctional lipid metabolism to AD pathogenesis in humans remain to be identified. Our Unit seeks to fill this gap by systematically characterizing lipid-related abnormalities throughout the full spectrum of AD, with the long-term goal of identifying new therapeutic leads and new approaches for preventing or treating AD and related neurodegenerative diseases. Approach With these goals in mind, we are developing and applying advanced immunohistochemistry (IHC) and multiplex-IHC protocols to simultaneously label dozens cellular and molecular markers in rapidly collected and rapidly processed human tissue specimens representing the full spectrum of AD-type pathology (from healthy aging to Mild Cognitive Impairment (MCI) to AD), in collaboration with D. Maric (Intramural NINDS). The spatial resolution and breadth of markers afforded by this approach are advancements over conventional approaches which typically provide either a much more limited set of markers, or lack the spatial resolution and context provided by concurrent labeling of cellular and architectural markers. Cellular and molecular markers included in this project can be classified into four general categories: (1) cellular and molecular architectural (non-pathological) markers; (2) classic AD-type pathological markers (i.e. amyloid oligomers and plaques, truncated and hyperphosphorylated tau); (3) emerging AD-type pathological markers (i.e. immune abnormalities, mitochondrial dysfunction, senescence); and (4) a broad range of markers to delineate lipid-related molecular pathways and derangements. Accomplishments We have made major progress in designing and implementing rigorous antibody validation protocols and completed several 60-plex (60 cellular and molecular markers) studies in AD spectrum cohorts including hippocampus, entorhinal cortex, and brainstem, including an expanded set of validated lipid metabolism and neurodegeneration markers. We completed RNA-protein codetection and multi-epitope protein labeling in additional subset of these specimens to assist in antibody validation. We also completed conventional single-marker IHC and western blot analyses to assist in antibody validation and marker quantitation. Findings from this helped form the basis for a unifying hypothesis underlying Alzheimer's disease. A manuscript containing these results and this novel unifying hypothesis was published in MedRxiv in 2021 and in the Journal of Alzheimer's disease in 2022. We are currently validating many additional antibodies and expanding to additional vulnerable brain regions. We are also using these datasets to help develop sophisticated artificial intelligence approaches to analyze the images and data. Summary This project provides high-quality, high-resolution images depicting lipid-related metabolic pathways and derangements throughout the spectrum of AD progression, in the context of CNS cytoarchitecture and more established AD-type pathologies. In addition, the construction and validation of CNS antibody libraries and protocols used for this project will provide a plug-and-play template allowing for comprehensive assessment of CNS pathological markers that can be applied to other tissues and diseases in future projects.