Abstract

Clinically, Alzheimer’s disease (AD) causes progressive decline in memory and cognitive function which ultimately leads to death. Given that this disease affects 1 in 8 Americans over the age of 65, there is a dire need for a better understanding of the underlying pathology of AD. Recent genetic studies have highlighted the central role of the innate immune system in AD by identifying several risk variants in genes that are predominantly expressed within microglia in the brain. Most notably, rare variants, such as the R47H, R62H and H157Y mutations, in the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) gene increase risk for late-onset AD (Guerreiro et al. 2013). TREM2 is a cell surface receptor expressed specifically by microglia in the brain. TREM2 signaling occurs through the immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptor DAP12 and its function supports diverse processes such as phagocytosis and clustering around debris, increased metabolic function, and lipid metabolism (Wang et al. 2015). Mounting evidence suggests that TREM2 function is age, context, and disease dependent and highlights the importance of understanding the type of pathology and pathology severity in the brains of patients with AD when therapeutically targeting TREM2 function. Further studies will be necessary to elucidate the effects of TREM2 variants and targeting TREM2 function within the context of Aβ-induced tau seeding and spreading as well as in the phase of tauopathy that is closely linked with neurodegeneration. Using a mouse model of Aβ amyloidosis (5XFAD) in which AD-tau is injected into the brain to induce Aβ-dependent tau seeding/spreading, we found that chronic administration of an activating TREM2 antibody increases peri-plaque microglial activation but surprisingly increases peri-plaque NP-tau pathology and neuritic dystrophy, without altering Aβ plaque burden. Additionally, through use of a 5XFAD/T2CV amyloidosis mouse model expressing the human TREM2 gene injected with AD-tau, we found that chronic administration of an anti-human TREM2 agonist or an anti-human TREM2 antagonist surprisingly both increased NP-tau pathology, total amyloid pathology and changed microglial reactivity in a sex and brain region dependent manner. Finally, I assessed the effects of another novel therapeutic approach for AD, xenon inhalation, on neurodegeneration, tau pathology, and neuroinflammation. As xenon inhalation is being explored in clinical trials as a potential therapeutic in various neurological conditions and neurodegenerative diseases, further understanding of the effects of xenon inhalation is important. We found that xenon inhalation reduced brain atrophy, rescued dentate gyrus layer thickness, improved nest building behavior but did not affect phosphorylated tau accumulation or disease specific conformational modification of tau. We found that astrocytes and microglia were less reactive and moreover, RNA sequencing revealed increased expression of neuronal and synaptic genes and decreased expression of inflammatory genes. Xenon inhalation compared to control air inhalation resulted in a neuroprotective effect, reduced the expression of inflammatory genes, and increased the expression of neuronal and synaptic genes in a mouse model of tau-mediated neurodegeneration. The studies demonstrate that effects of TREM2 and microglia are context dependent and differ based on disease severity, brain region, age, sex, mutation type and the types of pathologies present. All these factors need to be better studied and considered when designing TREM2 and microglial targeting therapies such as xenon inhalation with the goal of mitigating AD and other CNS disease associated pathologies. Prior to moving treatments into clinical trials, it is imperative to understand the effects of various therapeutics based on disease context.

Committee Chair

David Holtzman

Committee Members

Celeste Karch; Gregory Wu; John Cirrito; Tristan Qingyun Li

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

4-9-2025

Language

English (en)

Author's ORCID

https://orcid.org/0000-0002-3240-8989

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Available for download on Thursday, April 08, 2027

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