Fujita M, Gao Z, Zeng L, McCabe C, White CC, Ng B, Green GS, Rozenblatt-Rosen O, Phillips D, Amir-Zilberstein L, Lee H, Pearse RV 2nd, Khan A, Vardarajan BN, Kiryluk K, Ye CJ, Klein HU, Wang G, Regev A, Habib N, Schneider JA, Wang Y, Young-Pearse T, Mostafavi S, Bennett DA, Menon V, De Jager PL. Cell subtype-specific effects of genetic variation in the Alzheimer's disease brain. Nat Genet. 2024 Apr;56(4):605-614. Epub 2024 Mar 21 PubMed.
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Hong Kong University of Science & Technology
In this comprehensive work by the de Jager team, the authors addressed the effects of genetic variants on cell type- and cell subtype-specific gene expression in human brains. Using a large number of human brains and a wealth of genetic and new single-nucleus RNA-Seq datasets, they discovered a large number of “eGenes” at the cell type and cell subtype levels. Among them, a new gene variant is associated with the expression of the APOE gene but only in the microglia, not in astrocytes. Further, this event is linked to the greater amount of cerebral amyloid angiopathy (CAA), raising the possibility that microglial ApoE plays a key role in CAA development.
ApoE is known to seed parenchymal amyloids, with ApoE4 exhibiting a greater propensity than ApoE3. The experimental evidence obtained from animal modelling is consistent with human pathological outcomes whereby carriers of the APOE4 allele typically have earlier and more abundant amyloid. APOE is also linked to the abundance of CAA in both animal studies and humans, with APOE4 associated with more CAA than APOE3. How microglia are linked to CAA is not clear but studies from multiple labs including ours have shown that microglial ApoE plays an important role in limiting amyloid plaque development where ApoE4 microglia are less functional. That the new variant affecting microglial ApoE does not associate with parenchymal amyloids could be an indication that it is the APOE genotype and astrocytic ApoE rather than the relatively small changes in microglial ApoE that impact parenchyma amyloids. Nonetheless, the new association discovered here between microglial ApoE level and CAA warrants a test of a new hypothesis—that either microglial ApoE and/or the function of microglia impacted by ApoE level can affect CAA. Microglia could be responsible for seeding CAA as they do for parenchymal amyloids. They could also respond to CAA in a way analogous to, or different from, how they respond to amyloids. Alternatively, microglial ApoE diffused into the vasculature could impact CAA formation by interacting with Aβ to affect its catabolism, and/or it may interact with ApoE receptors to impact the function of vascular cells.
Overall, I applaud the tremendous work the authors put forward in this study using a large amount of data, combining genetic, epigenetic, and gene expression approaches in human brains. The new information generated from these association studies provide new clues for the functional neurobiologists who will need to validate the findings using animal, cellular, or other model systems.
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