UCSF

Apolipoprotein E4 (APOE4) is the strongest known genetic risk factor for late-onset Alzheimer’s disease (AD), however, its pathogenic mechanisms remain unclear. We performed in-depth studies on two intriguing, yet understudied, features of APOE4 pathogenesis to better understand their roles in promoting AD. First, APOE can be produced in a variety of cell types and may exert different pathological effects depending on its cellular source. We report a rigorous characterization of neuronal APOE4 effects on prominent AD-related pathologies by selectively removing APOE4 from neurons in an APOE4-expressing tauopathy mouse model. We found that removal of neuronal APOE4 led to a drastic reduction in Tau pathology, gliosis, neurodegeneration, neurodysfunction, and myelin deficits and eliminated disease-associated subpopulations of neurons, oligodendrocytes, astrocytes, and microglia that were enriched in APOE4-expressing tauopathy mice. Thus, neuronal APOE4 plays a central role in promoting the development of major AD pathologies. Second, APOE4 has been shown to be an important driver of Tau pathology, gliosis and degeneration in AD but the mechanisms underlying these APOE4-driven pathological effects remain elusive. We demonstrated in a tauopathy mouse model that APOE4 promotes significantly more nucleo-cytoplasmic translocation and release of high mobility group box 1 (HMGB1) from hippocampal neurons than APOE3. Treatment of APOE4-expressing tauopathy mice with HMGB1 inhibitors effectively blocked the nucleo-cytoplasmic translocation of HMGB1 and ameliorated the development of prominent APOE4-driven AD pathologies. Notably, treatment of APOE3-expressing tauopathy mice with HMGB1 inhibitors did not show significant beneficial effects on these pathological parameters. Thus, APOE4 drives Tau-mediated gliosis and degeneration by promoting neuronal HMGB1 release, and HMGB1 inhibitors represent a promising approach for treating APOE4-related AD and other tauopathies.