Distinct transcriptomic responses to Aβ plaques, neurofibrillary tangles, and APOE in Alzheimer's disease

INTRODUCTION: Omics 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 and APOE-linked differences remain unclear. METHODS: We performed laser capturemicrodissection of amyloid beta (A beta) plaques, the 50 mu m halo around them, tangles with the 50 mu m halo around them, and areas distant (> 50 mu m) from plaques and tangles in the temporal cortex of AD and control donors, followed by RNA-sequencing. RESULTS: A beta plaques exhibited upregulated microglial (neuroinflammation/ phagocytosis) and downregulated neuronal (neurotransmission/energy metabolism) genes, whereas tangles had mostly downregulated neuronal genes. A beta plaques had more differentially expressed genes than tangles. We identified a gradient A beta plaque > peri-plaque > tangle > distant for these changes. AD APOE epsilon 4 homozygotes had greater changes than APOE epsilon 3 across locations, especially within A beta plaques. DISCUSSION: Transcriptomic changes in AD consist primarily of neuroinflammation and neuronal dysfunction, are spatially associated mainly with A beta plaques, and are exacerbated by the APOE epsilon 4 allele.