PROJECT SUMMARY / ABSTRACT
Alzheimer’s disease (AD), the most common cause of dementia, is accompanied by progressive
neurodegeneration and stereotypic deposition of misfolded amyloid ß- (Aß) and tau proteins. However, the
basis for cellular dysfunction in AD is not well understood, underscoring an important need to broaden the
biologic scope of AD research. Technological advances, based on single-cell whole-genome sequencing
(scWGS) on frozen postmortem human brain tissue, now allow examination of previously inaccessible aspects
of the genome of individual cells in the brain. Recent research from our group has found that neurons in
individuals with AD show greater somatic single-nucleotide variants (sSNV) in their genomes than in
individuals without AD. Using mutational signature analysis, our study also found that the specific causes of
somatic mutations differed in AD, implicating oxidative stress and signal suggesting other cytopathologic
events.
This study aims to understand neuronal somatic mutation in AD at a deeper level, to probe how disease
progression and protein misfolding impact the burden and signatures of sSNV. The first aim will examine
neurons from individuals with different pathologic stages of AD. This will give us a better understanding of
when somatic mutations develop in disease, and whether certain mutagenic events occur with distinct timing in
the development of AD. The second aim will study how intracellular tau pathology relates to somatic mutation,
utilizing a novel method to separate individual nuclei according to tau tangle formation. In applying this method
to specific brain regions at specific pathologic stages at the forefront of AD progression, we will be able to
determine if somatic mutation is tied to tau pathology at the level of individual cells. In the final aim, we will test
whether Aß trigger somatic mutation, using a human iPSC-derived neuronal cellular model and incubation with
human brain-derived Aß oligomers.
With complementary approaches of novel scWGS technology, single-nucleus sorting, and specific human
tissues and and cellular systems, we will examine the mechanistic role of neuronal somatic mutations in AD.
This examination of the interplay between disease progression, protein misfolding, and the landscape of
somatic mutations will be an important step in understanding the molecular causes of AD. Moreover, the
capability of somatic mutational signature analysis to reveal previously unrecognized disease mechanisms
lends additional promise toward development of better treatments and cures.