Indiana University-Purdue University Indianapolis (IUPUI) / Alzheimer’s disease (AD) is typified by a robust microglial-mediated immune
response. Genetic studies have demonstrated that many genes that alter AD risk are
involved in the innate immune response and are primarily expressed in microglia. Among
these genes is phospholipase C gamma 2 (PLCG2), a critical element for various immune
receptors and a key regulatory hub for immune signaling. PLCG2 genetic variants are
associated with altered AD risk. The primary objective of this thesis was to determine the
role of PLCG2 in AD pathogenesis.
We observed significant upregulation of PLCG2 expression in three brain regions
of late-onset AD (LOAD) patients and a significant positive correlation of PLCG2
expression with amyloid plaque density. Furthermore, the differential gene expression
analysis highlighted inflammatory response-related pathways. These results suggest that
PLCG2 plays an important role in AD.
We systematically investigated the impact of PLCG2 haploinsufficiency on the
microglial response and amyloid pathology in the amyloidogenic 5xFAD mouse model.
The results demonstrated that Plcg2 haploinsufficiency altered the phenotype of plaqueassociated
microglia, suppressed cytokine levels, increased compact X34-positive plaque
deposition, and downregulated the expression of microglial genes associated with
immune cell activation and phagocytosis. Our study highlights the role of PLCG2 in
immune responses; loss of function of PLCG2 exacerbates the amyloid pathology of AD. Genetic studies demonstrated that the hypermorphic P522R variant is protective
and that the loss of function M28L variant confers an elevated risk for AD. Our results
demonstrated that PLCG2 variants modulate disease pathologies through specific
transcriptional programs. In the presence of amyloid pathology, the M28L risk variant
impaired microglial response to plaques, suppressed cytokine release, downregulated
disease-associated microglial genes, and increased plaque deposition. However,
microglia harboring the P522R variant exhibit a transcriptional response endowing them
with a protective immune response signature linked to their association with plaques and
Aβ clearance, attenuating disease pathogenesis in an amyloidogenic mouse model of AD.
Collectively, our study provides evidence that the M28L variant is associated with
accelerated and exacerbated disease-related pathology, and conversely, the P522R variant
appeared to attenuate disease severity and progression. / 2024-10-03
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/30360 |
| Date | 09 1900 |
| Creators | Tsai, Andy Po-Yi |
| Contributors | Oblak, Adrian L., Landreth, Gary E., Lamb, Bruce T., Liu, Yunlong, Mckinzie, David L., Nho, Kwangsik |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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