Distinct transcriptomic responses to Ab 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 capture microdissection of Ab plaques, the 50mm halo around them, tangles with the 50mm halo around them, and areas distant (>50mm) from plaques and tangles in the temporal cortex of AD and control donors, followed by RNA-sequencing. RESULTS: Ab plaques exhibited upregulated microglial (neuroinflammation) and downregulated neuronal (neurotransmission/energy metabolism) genes, whereas tangles had mostly downregulated neuronal genes. Ab plaques had more differentially expressed genes than tangles. We identified a gradient Ab plaque>peri-plaque>tangle>distant for these changes. AD APOEe4 homozygotes had greater changes than APOEe3 across locations, especially within Ab plaques. DISCUSSION: Transcriptomic changes in AD consist primarily of neuroinflammation and neuronal dysfunction, are spatially associated mainly with Ab plaques, and are exacerbated by the APOEe4 allele. Overall design: Abeta plaques, the 50um halo around them, tangles with a 50um halo around them, and areas distant (>50um) from plaques and tangles in the temporal cortex of 10 Alzheimer's disease cases (n=5 APOEe4/e4, n=4 APOEe3/e3, and n=1 APOEe3/e4) were profiled, along with 8 age- and sex-matched control donors