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Alzheimer’s disease (AD) is neuropathologically defined by the accumulation of extracellular amyloid β (Aβ)-containing plaques, intraneuronal hyperphosphorylated tau protein aggregates, and synaptic and neuronal loss, which together contribute to cognitive and functional decline. Despite these stereotyped features, AD has a complex etiology and presents along a spectrum of severity and pathology (1). This is underscored by the fact that genome-wide association studies have identified over 70 genetic loci that contribute to AD risk (2). Despite the genetic heterogeneity that exists in AD, capturing the genetically complex drivers of AD is experimentally challenging. Induced pluripotent stem cell (iPSC) technology provides a unique opportunity to define the genetic and molecular underpinnings of “person-specific” variation in brain neuropathology and cognition. We have generated iPSCs from over 100 individuals across the Rush Alzheimer’s Disease Center (RADC) Religious Orders Study (ROS), Memory and Aging Project (MAP), and Minority Aging Research Study (MARS) cohorts (3-4). Data collected from participants in these cohorts includes genome sequencing, longitudinal cognitive scores, quantitative neuropathology, and multi-omic characterization of brain tissue. Our approach leverages these rich datasets to cross-validate convergent molecular systems disrupted between our cellular models and processes in the brain of the individuals from whom they were derived. Our preliminary studies examined synapse function across a small discovery cohort of iPSC derived neurons (iNs) from 23 individuals with either no cognitive impairment or AD. This analysis revealed subsets of AD iNs with dysfunction in synaptic vesicle (SV) release. This was particularly evident in those AD iNs carrying the disease risk haplotype for SORL1, a sorting protein involved in retromer trafficking(5) and Aβ clearance(6). Moreover, expression of synaptic proteins (VGLUT2, HOMER1, UNC13A, etc.) within both our discovery cohort iNs as well as postmortem brain tissue showed significantly increased expression in individuals with AD diagnosis. I hypothesize that the dysregulated synaptic networks observed in our proteomics data(4) represent functional consequences at the synapse, that this phenotype presents stronger in specific subsets of the AD population and is driven in part through dysregulated SORL1. To test this hypothesis, I am investigating the molecular and cellular mechanisms that lead to synaptic dysfunction in subsets of LOAD, exploring the role of SORL1 and other LOAD genetic risk variants in normal synapse function and in AD. Ultimately this work will provide valuable insight into the role hyperactivity plays in AD and contribute a deeper understanding of the fundamental mechanisms governing normal neuronal activity.
References:
1. Kimberly TW, et al. γ-Secretase is a membrane protein complex comprised of presenilin, nicastrin, aph-1, and pen-2. (2003)
2. Bellenguez, C et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. (2022)
3. Bennett DA, et al. Religious Orders Study and Rush Memory and Aging Project. (2018)
4. Lagomarsino VN, et al. Stem cell-derived neurons reflect features of protein networks, neuropathology, and cognitive outcome of their aged human donors. (2021)
5. Andersen OM, et al. . Risk factor SORL1: from genetic association to functional validation in Alzheimer’s disease. (2016)
6. Hung C, et al. SORL1 deficiency in human excitatory neurons causes APP-dependent defects in the endolysosome-autophagy network. (2021)
