Abstract Details

Title Microglial Morphology and Gene Expression Are Altered in Individuals Resilient to Alzheimer’s Disease

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P3 - Poster Session 3 (11:45 AM-12:45 PM)

Poster/Presentation
Number 3-006

Objective Determine whether differences in microglial function exist in Alzheimer’s disease (AD) resilience.

Background AD is the most common neurodegenerative disease and a major challenge given the absence of any therapy that halts or reverses cognitive decline. AD resilience, defined as harboring the neuropathological hallmarks of AD (i.e., amyloid-β plaques and neurofibrillary tangles) but lacking the cognitive decline associated with dementia, represents an opportunity to identify novel mechanisms that may be leveraged to develop AD treatments. Microglia, the innate immune cells of the central nervous system, are linked to AD pathogenesis and may mediate aspects of AD resilience.

Design/Methods Autopsy samples of dorsolateral prefrontal cortex were collected from a cohort of 35 human individuals with average age at death >80 years and post-mortem interval <8 hours. The cohort was comprised of 15 resilient individuals (cognitively unimpaired with AD neuropathology), 10 affected individuals (cognitively impaired with AD neuropathology), and 10 resistant controls (cognitively unimpaired without AD neuropathology) for the single-nucleus RNAseq, and 17 resilient, 10 affected, and 8 resistant individuals for the immunohistochemistry (IHC) dataset. Single-nucleus RNAseq of grey matter nuclei enriched for microglia using PU.1 FANS was used to measure gene expression profiles. IHC was done on separate sections to investigate microglial morphology with confocal microscopy.

Results Single-nucleus RNAseq demonstrated the expected diversity of microglial states, including multiple forms of homeostatic gene expressing microglia, as well as differences in the enrichment of certain microglial states in resilient versus affected individuals. Additionally, we found differences in gene expression between resilient and affected individuals within states. Confocal microscopy revealed a shift in microglial morphology between cohort groups.

Conclusions These results suggest that there are differences in microglial characteristics in AD resilience. Further characterization may identify targets that could be leveraged to develop new treatments that alter microglial states to mitigate AD-associated cognitive decline.

Authors/Disclosures
Nicholas Karagas, MD (UW- Neurology Residency) PRESENTER	An immediate family member of Dr. Karagas has received personal compensation for serving as an employee of Thirty Madison. An immediate family member of Dr. Karagas has received personal compensation in the range of $100,000-$499,999 for serving as an officer or member of the Board of Directors for Thirty Madison. An immediate family member of Dr. Karagas has stock in Thirty Madison.
Alexandra N. Sotelo	Mrs. Sotelo has nothing to disclose.
Corbin S. Johnson, PhD	Dr. Johnson has nothing to disclose.
Nikhil H. Saha	Mr. Saha has nothing to disclose.
Vanessa K. Souders	Miss Souders has nothing to disclose.
Sainath Suryakant Mamde	Mr. Mamde has nothing to disclose.
Isabel Smith	Ms. Smith has nothing to disclose.
Aquene N. Reid	Mrs. Reid has nothing to disclose.
Kevin Green	Mr. Green has received personal compensation for serving as an employee of Deverra Therapeutics .
Arti Parihar, PhD	Dr. Parihar has nothing to disclose.
Dirk Keene, MD, PhD	Dirk Keene, MD, PhD has received publishing royalties from a publication relating to health care.
Thomas J. Grabowski, MD (University of Washington)	The institution of Dr. Grabowski has received research support from NIH.
Caitlin S. Latimer, MD, PhD	Dr. Latimer has nothing to disclose.
Kevin Z. Lin, PhD	Dr. Lin has nothing to disclose.
Suman Jayadev, MD (University of Washington Medical Center)	Dr. Jayadev has nothing to disclose.
Katherine Prater	The institution of Katherine Prater has received research support from Warren Alpert Foundation Distinguished Scholars Award.

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