Saturday, September 7, 2024
9/7/2024
Endosomal dysfunction is a well-accepted cell biological feature in Alzheimer’s disease (AD). However, biomarkers reflecting endosomal traffic defects are still lacking. Current imaging and cerebrospinal fluid (CSF) AD biomarkers focus primarily on the histopathology of the disease—that is, biomarkers that are linked to neurofibrillary tangles and amyloid plaques. This proposal is designed to expand this focus to develop biomarkers of the ‘cell biology’ of AD. Such biomarkers could potentially accelerate drug discovery, as therapeutic interventions are currently being developed that target endosomal trafficking defects in AD. Genetic and cell biology studies have previously linked the endosomal trafficking assembly Retromer to AD pathology. Most notable are deficiencies and rare mutations in retromer’s core protein, VPS35, and retromer’s receptor, SORL1. Depletion of either VPS35 or SORL1 mimics the core cytopathology in AD, enlarged endosomes in neurons, with concomitant mis-trafficking of endosomal cargoes. In an effort to characterize defects in the endocytic pathway resulting from retromer dysfunction, we recently completed a proteomic screen of CSF of VPS35 knock-out (KO) mice and control littermates. Among the proteins found elevated in the CSF of VPS35 KO mice were well established β-secretase BACE1 substrates, includingAPP (Amyloid Precursor Protein); APLP1/2 (Amyloid Beta Precursor Like Proteins 1 and 2); and CHL1 (Neuralcell adhesion molecule L1-like protein). Two of these proteins --APLP1 and CHL1-- were further validated inmouse CSF, and human CSF from cognitively healthy participants and prodromal AD patients. Collectively, our studies suggest BACE1 substrates as potential biomarkers of retromer-dependent endosomal dysfunction. However, since VPS35 is implicated in other neurodegenerative disorders, including Parkinson’s disease (PD), these new biomarkers may not be specific to AD. Therefore, relying on these exciting findings, but moving towards the development of a panel of biomarkers reflecting endosomal trafficking defects that are specific to AD, we will examine SORL1 mouse models and human pluripotent stem cell (hPSC) SORL1-derived neurons as a new source of biomarkers of endosomal trafficking. We will also investigate exosomes as an additional source of biomarkers of endosomal defects. Lastly, since Sorl1 protein levels are altered in AD and CSF from AD patients, we will examine SORL1 CSF levels as a potential biomarker for AD. Completion of this study will provide evidence that SORL1-dependent endosomal trafficking is a new source of biomarkers for AD. Moreover, we predict that the extensive studies here proposed will identify a unique and specific endosomal biomarker of the “cell biology” of AD.
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