Sunday, May 11, 2025
5/11/2025
Influence of APOE4 genotype on microglial pathobiology and tau pathology after repetitive mTBI - One of the hallmark, chronic, features of repetitive mild TBI (r-mTBI) is the deposition of phosphorylated tau in neurons. Tau lesions are also one of the main hallmark features of ADRD. It remains unknown what specific molecular triggers precipitate the path towards this distinct TBI related neurodegenerative phenotype. The E4 allele is a major genetic risk factor for AD; individuals carrying 1 copy have a 2-3 fold risk for AD, while those with 2 copies have a 15-fold risk compared to E3 carriers. Despite some contradictory studies, the E4 allele has long been associated with a poor outcome after TBI, but the role played by APOE in response to TBI is still unknown and well-designed longitudinal studies are needed. Conducting such studies in humans remains challenging as epidemiological and prospective data are lacking, plus the heterogeneity of TBI etiology, including (but not limited to) severity level, age, comorbidities and time post-TBI, present an enormously confounding problem. Thus, the best way to address this question is in translationally relevant, well characterized and controlled animal models, wherein key predisposing genetic factors can be targeted and expressed, and findings from longitudinal analyses can be related to the limited autopsy information from human TBI cases who have died at different timepoints after their injury. We have developed and characterized such mouse models of r-mTBI, which recapitulate many features of human TBI pathology. In recent work, we have exposed human APOE-targeted replacement mice (APOE-TR), mice humanized for Tau (TauKI) and crosses of these mice (E-Tau) to our r-mTBI paradigm, and observe TBI-dependent pTau pathology. From these studies we have also revealed that the E4 allele augments the proinflammatory microglial response and Tau pathology in injured mice compared to E3. APOE is upregulated in disease associated microglia, which has been reported in AD brains. In our r-mTBI model we have also confirmed an increase in microglial specific APOE gene expression. Disease associated microglia have been reported to drive the outcome and pace of APOE4-dependent neurodegeneration in AD transgenic models; yet very little is known about their contribution in driving APOE4 mediated effects after r-mTBI. We will address these unknowns using mouse models expressing human forms of APOE/Tau, and expose them to our r-mTBI paradigm to address these timely and under-studied interactions. We will first expose these models topharmacological manipulation of microglia using depopulation/repopulation paradigms to delineate their contribution to the APOE influence on r-mTBI pathogenesis and tau pathology. In the next part of the study, we will use an inducible APOE-KI model to genetically manipulate to delineate their contribution to the APOE influence on microglial TBI mediated neurodegeneration, tau pathology and behavioral outcome. microglia specific APOE expression transcriptomic phenotypes and ex vivo functional activities, We will finally compare TBI-dependent microglial transcriptomic responses in the presence or absence of APOE deletion in this model to reveal microglial specific targets that correlate with favorable outcomes after r-mTBI and represent novel therapeutic targets. We will confirm the translational relevance of our targets in r-mTBI/control autopsy cases from different APOE backgrounds. Our future work will interrogate the functional and therapeutic roles of these targets. This study is much needed as a first step in deciphering the role of APOE4 in microglia pathobiology after r-mTBI, which is currently under-investigated.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).