Hayk Davtyan (United States of America)
UNIVERSITY OF CALIFORNIA, IRVINE
Institute for Memory Impairments & Neurological Disorders
A major focus of my research centers around the design and development of immunotherapeutic approaches for treating Alzheimer’s disease (AD) and related disorders. My interest and expertise in this area include development and studies of various types of AD and Parkinson Disease (PD) vaccines, including DNA and protein vaccines, viral vector, epitope-based vaccines, as well as strategies to enhance vaccine efficacy (chemokines, molecular adjuvants, etc.). I am also extremely interested in understanding the role of the adaptive immune system in AD and whether neuroprotective autoantibodies may slow or even prevent the development of AD. Over the course of my career, I have successfully collaborated with many researchers, producing over 45 peer-reviewed publications to date. While working on these projects, I have demonstrated skills that enabled me to lead the process and successful completion of several projects: creation of research plans, timelines and workable budgets, with emphasis on setting realistic and informative goals. My current project at UCI MIND we developed a fully-defined approach to differentiate patient-derived iPS cells into microglia and is using these cells in conjunction with CRISPR gene editing and chimeric xenotransplantation models to examine the impact of AD-associated mutations in TREM2, MS4A6A and PLCG2 on human microglial function.

Presenter of 1 Presentation

 Conference Calendar

UNDERSTANDING HUMAN TREM2-DEPENDENT MICROGLIAL RESPONSES TO ALZHEIMER’S DISEASE PATHOLOGY IN VIVO WITH CHIMERIC MICE

Session Name
0390 - MICROGLIA, TREM2, NEUROINFLAMMATION (ID 87)
Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
04:15 PM - 06:00 PM
Room
ONSITE: 113
Lecture Time
04:45 PM - 05:00 PM
Presenter

Abstract

Aims

Genome wide association studies have identified many Alzheimer’s disease (AD) risk genes that are highly expressed by microglia. Loss-of-function mutations in one such gene, TREM2 (Triggering receptor expressed on myeloid cells-2) have been shown to increase Late-onset AD risk by 2-4-fold. Studies of TREM2 knockout mice have provided consistent evidence that TREM2 is critically involved in the ability of microglia to sense and respond to beta-amyloid plaques. Yet many questions remain regarding whether human TREM2 knockout microglia exhibit similar or perhaps additional functional deficits.

Methods

To further examine the impact of TREM2 deletion on human microglia, we used CRISPR to generate TREM2-knockout (TREM2-KO) induced pluripotent stem cells (iPSCs). Isogenic wildtype and TREM2-KO iPSCs were differentiated into hematopoietic progenitors (HPCs) and transplanted into postnatal immunodeficient AD mice (hCSF1-5xFAD). Six months later, human microglia were isolated from chimeric mice brains and examined via single-cell RNA sequencing and bulk proteomic analysis.

Results

Analysis of RNA sequencing and proteomic datasets reveals significant and novel impacts of TREM2 deletion on the response of human microglia to beta-amyloid pathology. Examination of these complementary datasets identified both immune- and synapse-related co-expression networks that are significantly altered between TREM2 genotypes in AD mice. RNA sequencing further reveals distinct changes in disease associated microglia (DAM) and regulators of G protein signaling (RGS) cell populations with varying TREM2 genotypes.

Conclusions

Taken together, these data reveal important new information about the transcriptional and proteomic changes that occur within human microglia in response to amyloid pathology and loss of TREM2 expression.

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