Transcriptomic assessment of pathology in PD with dementia and dementia with Lewy Bodies using iPSC neurons and brain tissue of the same individuals

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PROJECT ABSTRACT Lewy Body dementia (LBD) is a spectrum disease that includes dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). The two dementias share neuropathological characteristics of alpha- synuclein (a-syn) inclusion in so called Lewy bodies, in addition to variable pathologies related to Alzheimer’s disease – amyloid-beta (Ab) plaques and/or neurofibrillary tangles (NFT) of hyperposphorylated tau. One of the most distinct differences between PDD and DLB is the temporal occurrence of motor impairments relative to cognitive impairments. This often challenges an accurate diagnosis and consequently appropriate patient enrollment in clinical trials, patient care and existing symptomatic treatment. To better understand the distinct temporal progression of these two dementias we propose to utilize patient-derived induced pluripotent stem cell (iPSC) culture models – a disease model system that offers personalized patient analyses and drug screening. To ensure that this model system accurately reflects the individual patient’s disease pathogenesis, we propose to generate iPSCs differentiated into neurons from individuals from which we also have postmortem autopsy tissue available. This provides us with the unique opportunity to directly compare transcriptomics and disease pathology from brain tissue and differentiated iPSC-neurons from the same individual. In addition, we are able to monitor and characterize disease progression in PDD compared to DLB in a temporal manner. We hypothesize that iPSC-neurons from PDD patients will show phenotypic differences in their temporal disease progression compared to DLB patient iPSC-neurons. We further hypothesize that there are similarities of gene expression profiles and disease pathologies between differentiated iPSC-neurons and primary autopsy tissue obtained from the same individuals. To test this hypothesis we will perform single nuclei multi-omics sequencing (snRNA- and ATAC seq) from PDD, DLB and healthy control autopsy brain tissues (Aim 1). In Aim 2, we will differentiate PDD and DLB iPSCs (from the same individuals as Aim 1) into cortical forebrain neurons to generate a disease-specific neuronal transcriptome profile and to examine PD and dementia-related disease phenotypes. These studies will for the first time study the transcriptome profile of PDD and DLB, examine cellular disease phenotypes in a temporal manner and address the disease mechanisms of LBD in this spectrum disorder. Additionally, this work will provide novel opportunities for drug target identification with the hope of identifying novel therapeutics and biomarkers specific for each of the two disorders. This in return will facilitate the much- needed improvement of disease diagnosis and management of PDD and DLB patients.