ALZHEIMERS RESEARCH PROJECT: Dysfunctional lipid metabolism in Alzheimer's Disease

National Institute On Aging

Investigators

Linked publications, trials & patents

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 the pathogenesis of sporadic forms of AD 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 developed and are applying advanced immunohistochemistry (IHC) and multiplex-IHC protocols to simultaneously label dozens of 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 information 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, morphological and cytoarchitectural 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, neuro-inflammatory markers); (3) emerging AD-type pathological markers (e.g. Reelin signaling partners, others); 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 100-plex (100 cytoarchitectural and molecular markers) studies in AD spectrum cohorts including hippocampus, entorhinal cortex, amygdala 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 provided evidence to support for a new mechanistic paradigm and unifying hypothesis underlying Alzheimer's disease and provided evidence to support a novel integrated hypothesis to explain pTau associated neurodegeneration in human sporadic AD (published in 2021-2023). Our alternative, unifying AD model provided a plausible alternative to the prevailing hypotheses (amyloid cascade and Tau prion-like propagation), and has suggested novel strategies for preventing and treating sporadic AD in humans. These efforts also assisted in characterizing novel mechanism-based biomarkers for synapse disassembly in Alzheimer's disease. We are currently validating many additional antibodies and expanding to additional vulnerable brain regions in other neurodegenerative diseases. We are also using these datasets to help develop new approaches to analyze the images and data. Summary This project provides high-quality, high-resolution images depicting lipid and lipoprotein-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. Application of these tools alongside other studies in our group have provided the basis for a new way of looking at sporadic AD in humans.