UC Irvine

Extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated tau are hallmark pathologies of Alzheimer’s disease (AD), accompanied by neuronal loss and chronic neuroinflammation. While Aβ plaques precede cognitive decline and NFT formation, NFTs correlate more closely with neuronal death and clinical symptoms. Crosstalk between Aβ plaques and tau pathology likely involves immune responses, with microglia—key brain immune cells—playing a central role. Microglial morphological changes align with AD progression, and genome-wide association studies (GWAS) have identified microglia-related risk genes, including TREM2 and APOE, as major contributors to late-onset AD (LOAD). TREM2, a microglial receptor, and APOE, a lipid transport glycoprotein and TREM2 ligand, are both implicated in disease-associated microglia (DAM) responses in mice. Understanding how genetic variants of TREM2 and APOE affect AD outcomes is crucial. Therefore, this dissertation investigates the impact of the TREM2 R47H (detrimental) and APOE R136S (APOE3Ch, protective) variants on AD pathology using 5xFAD (amyloidosis) and PS19 (tauopathy) mouse models.To study the detrimental TREM2 R47H variant, a new Trem2R47H NSS mouse model was developed to avoid the confounding effects of cryptic splicing. In the presence of the 5xFAD transgenic allele, I found that these mice exhibited early-stage reductions in microglial responses to plaques, increased axonal damage, and impaired inflammatory activity, but preserved synaptic plasticity. At advanced stages, the 5xFAD Trem2R47H NSS mice showed unique interferon-related gene expression, sustained neuronal damage, and exacerbated synaptic loss. This highlights a stage-dependent loss of function and altered immune signature associated with the R47H variant. The APOE3Ch variant, identified as protective against autosomal dominant AD, was introduced into mouse Apoe (ApoeCh) for analysis. In 5xFAD mice, I found that ApoeCh enhances DAM phenotypes, and reduces plaque load, dystrophic neurites, and plasma neurofilament light chain levels. Conversely, in PS19 mice, ApoeCh dampens microglial and astrocytic responses, and mitigates synaptic and myelin loss, but does not reduce tau accumulation or phosphorylation. Comparative analyses revealed distinct DAM signatures, with antigen presentation genes upregulated in tauopathy models, highlighting pathology-specific microglial programming. Proteomic studies showed mitochondrial protein increases in 5xFAD;ApoeCh mice, but reductions in mitochondrial and translation-associated proteins in PS19 mice. These findings suggest that the protective effects of APOE3Ch involve microglial modulation tailored to specific AD pathologies, driven by receptor interactions and microglial reprogramming. Together, these studies demonstrate how TREM2 and APOE variants affect AD pathogenesis through microglial responses, likely driven by changes in receptor/ligand binding activities, with implications for targeting immune pathways in AD therapies.