Abstract
ABSTRACTINTRODUCTIONOmics studies have revealed that various brain cell types undergo profound molecular changes in Alzheimer’s disease (AD) but the spatial relationships with plaques and tangles andAPOE-linked differences remain unclear.METHODSWe performed laser capture microdissection of Aβ plaques, the 50μm halo around them, tangles with the 50μm halo around them, and areas distant (>50μm) from plaques and tangles in the temporal cortex of AD and control donors, followed by RNA-sequencing.RESULTSAβ plaques exhibited upregulated microglial (neuroinflammation/phagocytosis) and downregulated neuronal (neurotransmission/energy metabolism) genes, whereas tangles had mostly downregulated neuronal genes. Aβ plaques had more differentially expressed genes than tangles. We identified a gradient Aβ plaque>peri-plaque>tangle>distant for these changes. ADAPOEε4 homozygotes had greater changes thanAPOEε3 across locations, especially within Aβ plaques.DISCUSSIONTranscriptomic changes in AD consist primarily of neuroinflammation and neuronal dysfunction, are spatially associated mainly with Aβ plaques, and are exacerbated by theAPOEε4 allele.
Publisher
Cold Spring Harbor Laboratory
Cited by
2 articles.
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