Defining the Spatial Relationship Between Early Endosomal Abnormalities, Amyloid Pathology and Early-Stage Tau Hyperphosphorylation in Primate Models of Sporadic Alzheimer's Disease

About This Grant

Sporadic Alzheimer’s disease (sAD) affects millions worldwide, yet the earliest molecular events that drive its progression remain poorly understood. Hallmark pathologies—amyloid-β (Aβ) plaques and tau neurofibrillary tangles (NFTs)—develop decades after subtle cellular changes have already begun. One of the strongest emerging biomarkers of preclinical AD is soluble phosphorylated tau at threonine 217 (pT217Tau), which appears in cerebrospinal fluid and plasma years before overt symptoms or brain pathology. Endosomal enlargement, a robust early abnormality linked to Aβ42 generation from amyloid precursor protein (APP), is also present in at-risk individuals. However, the spatial and temporal relationship between early-stage tau hyperphosphorylation, amyloid pathology, and endosomal changes has never been directly visualized in human or nonhuman primate brains. This gap limits the development of early diagnostic tools and therapies. The overall goal of this project is to define the earliest molecular convergence points between soluble pT217Tau, APP/Aβ42, and endosomal abnormalities across human postmortem tissue, aging nonhuman primates, and human induced pluripotent stem cell (hiPSC)–derived neurons. This multiscale approach is uniquely enabled by (1) postmortem human tissue spanning Braak stages I–VI, (2) perfusion-fixed rhesus macaque brains that preserve soluble phosphorylation states and native ultrastructure, and (3) mechanistic testing in hiPSC-derived neurons including SORL1-deficient lines, which model genetic risk for endolysosomal dysfunction. Aim 1 will define the spatial relationship between pT217Tau, endosomal enlargement, and APP/Aβ42 in early human AD stages using quantitative immunofluorescence across vulnerable (entorhinal cortex, hippocampus, dorsolateral prefrontal cortex) and resilient (primary visual cortex) regions. Aim 2 will examine age-related associations between pT217Tau, APP/Aβ42 and endosomal abnormalities in rhesus macaque cortex, applying dual-label immuno- electron microscopy to achieve nanoscale resolution of tau–endosome interactions. Aim 3 will determine whether promoting tau hyperphosphorylation in hiPSC-derived neurons is sufficient to induce endosomal abnormalities and altered APP/Aβ42 trafficking, with particular emphasis on retromer dysfunction in SORL1- deficient cells. By combining observational and experimental systems, this project will directly test the hypothesis that soluble pT217Tau—but not fibrillar tau—is preferentially associated with APP/Aβ42-containing endosomes in neurons of vulnerable cortical regions, and that this phenotype can be recapitulated in vitro. The proposed studies are highly innovative in their integration of human, nonhuman primate, and cellular models, and in their use of cutting-edge nanoscale imaging to capture disease processes at unprecedented resolution. Results will illuminate the etiology of sAD pathogenesis, identify the earliest cellular events linking tau and amyloid pathology, and reveal new targets for early intervention. Ultimately, this work has the potential to transform how we detect and treat sAD by focusing on the earliest and potentially reversible stages of the disorder.