Abstract

Alzheimer’s disease (AD) pathology is characterized by the accumulation of amyloid beta (Aβ) protein aggregates, accompanied by prominent microglial activation. Genetic studies have highlighted microglia as central regulators of AD progression. During disease progression, microglia proliferate and become activated in response to Aβ aggregates, forming cellular barriers that encase and engulf Aβ plaques. However, the cellular mechanisms that govern how microglia cope with chronic proteotoxic stress and modulate amyloid pathology remain incompletely understood. Autophagy and the unfolded protein response (UPR) are key pathways that mitigate cellular stress and preserve homeostasis. My dissertation dissects microglial responses to amyloid pathology through three aspects: autophagy, UPR signaling, and TREM2-DAP10 innate immune signaling pathways. I examined the role of microglial autophagy by specifically depleting ATG7, a key component of the autophagy pathway, in microglia of 5xFAD mice. We demonstrated that Atg7 deficiency led to a significant decrease of microglia density in the cortex; it also dampened microglial response against amyloid pathology. Single-cell RNA sequencing analysis and biochemical assays suggested that Atg7-deficient microglia reduced UPR while upregulated reactive oxygen species (ROS)-related signatures. We further showed that these changes lead to lipoperoxidation and ferroptosis of microglia, which eventually lead to reduced microglia numbers. In aged mice without Aβ buildup, UPR reduction and increase of oxidative damage induced by Atg7 deletion did not impact microglia numbers. We conclude that reduced UPR and increased oxidative stress in Atg7-deficient microglia lead to ferroptosis when exposed to proteotoxic stress from Aβ plaques. However, these microglia can still manage misfolded protein accumulation as they age. These observations motivated us to investigate the function of UPR in microglia. Previous research has demonstrated that UPR is critical for microglia to elicit proinflammatory responses and secrete cytokines. But the role of microglia UPR in neurodegeneration is still poorly understood. We focused on the IRE1-Xbp1 branch of UPR pathways and examined its function in microglia in the contexts of amyloid pathology and cuprizone-induced demyelination. Surprisingly, disruption of this pathway did not result in significant changes in disease pathology in either model. Microglia-specific deletion of IRE1α has minimal effects on amyloid burden, microgliosis, and demyelination-induced inflammation, indicating that IRE1α is largely dispensable for microglial responses in these settings. These results suggest functional redundancy among UPR branches or context-dependent engagement of UPR signaling in microglia during neurodegeneration. In addition to protein homeostasis, innate immune signaling, especially TREM2 signaling, also plays a critical role in microglia function. The TREM2-DAP12 signaling has been well characterized as essential for maintaining microglial metabolic fitness, supporting the development of disease-associated microglia (DAM) and their effective responses against amyloid pathology. In contrast, the role of DAP10, an alternative adaptor protein of Trem2, remains poorly understood. We examined the effects of DAP10 deficiency in microglial responses against AD using DAP10-/- 5xFAD mice across different pathology stages. Our findings revealed that DAP10-deficient microglia exhibit impaired plaque encasement during early stage, this deficit exacerbates amyloid pathology and enhanced microgliosis in the late stage. Notably, these phenotypes differ from those observed in Trem2/DAP12-deficient mice, highlighting a distinct and stage-specific role for DAP10 in modulating microglial responses to AD pathology. Together, this work establishes microglial autophagy, cellular homeostasis, and innate immune signaling as key determinants of microglial survival, activation state, and protective function during Alzheimer’s disease progression.

Committee Chair

Marco Colonna

Committee Members

Christina Stallings; Gregory Wu; Marco Sardiello; Qingyun Li

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Immunology)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

4-15-2026

Language

English (en)

Author's ORCID

https://orcid.org/0009-0003-7810-3827

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Available for download on Thursday, April 13, 2028

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