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