PROJECT SUMMARY
Alzheimer’s disease (AD) is a devastating neurodegenerative condition that it is estimated to affect 16 million
Americans by 2050. AD is mixed proteinopathies (e.g., amyloid-β (Aβ) aggregation, tau neurofibrillary tangles,
and TDP-43 inclusions) and selectively affect certain regions of the brain (e.g., neocortex and hippocampus)
with complex pathophysiology.
and characterization of specific
Although multiple studies have focused on genetic factors for AD, the delineation
neuronal and glial cell populations with enriched vulnerability to proteinopathy in
AD remains unknown. Our team has demonstrated that single-cell/nucleus multi-omics (snRNA-seq/snATAC-
seq) can be used to investigate both “normal” and “pathological” neuronal and glial subpopulations from human
post-mortem brains and we have also established a large human brain biobank with diverse proteinopathies
(including Aβ, tau, TDP-43 and others). Moreover, we have demonstrated how targeting proteinopathy-specific
networks, such as acetylated Tau and synergistic proteinopathy networks shared by Tau and Aβ, can identify
repurposable treatments (e.g., sildenafil and diflunisal) for AD. Our preliminary snRNA-seq and snATACT-seq
analyses of human post-mortem cerebellum regions from 7 individuals (n=4 [AD] and n=3 other dementia cases)
have revealed unique neuronal and glial cell populations and genes/networks when comparing to traditional
snRNA-seq data from neocortex and hippocampus. Our integrative snRNA-seq data analysis has also identified
disease-relevant microglial subtypes, including microglia containing amyloid-b/phosphor-tau, as well as microglia
enriched in expression of pro-inflammatory markers, using deep generative models. We therefore hypothesize
that comprehensive characterization of human neuronal and glial cell genomic and epigenomic signatures and
networks that are vulnerable to proteinopathies will help to identify novel mechanistic pathways and disease-
modifying treatments. In Aim 1, we will generate comprehensive multi-ome data of human neuronal and glial
cells vulnerable to AD proteinopathies. We will use a sample pooling snRNA-seq/snATAC-seq technology to
analyze human post-mortem neocortex, hippocampus, and cerebellum with varying degrees of proteinopathy
severity (amyloid-b, p-tau and TDP-43) and age-, sex- and APOE-matched cognitive healthy controls available
from the Northwestern Alzheimer’s Disease Research Center. In Aim 2, we will test the hypothesis that neuronal
and/or glial cell-specific genomic/epigenomic signatures and networks identify the molecular mechanism(s) of
vulnerability and resilience in AD. These multimodal data analyses will integrate large snRNA-seq/snATAC-seq
profiles with existing whole genome-sequencing data from the Alzheimer’s disease sequencing project (ADSP).
In Aim 3, we will test the hypothesis that selective cellular vulnerability linked to genes/networks can be targeted
via pharmacologic treatment to slow progression of AD-like disease in animal models. Successful completion of
our project will identify new treatment opportunities that target specific neuronal and/or glial cell-specific
risk/resilience genes and networks that confer vulnerability to proteinopathies in AD and other dementias.
