Rosemarie J. Jackson, United States of America
Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease NeurologyAuthor Of 1 Presentation
EFFECT OF APOE ALLELES ON THE GLIAL TRANSCRIPTOME IN NORMAL AGING AND ALZHEIMER’S DISEASE
Abstract
Aims
Recently, APOEε4 has been implicated in aging and other neurodegenerative diseases suggesting broader Aβ-independent mechanisms, among them glial responses. To understand these mechanisms, we aimed to investigate the differental effect of APOE alleles on the microglia and astrocyte transcriptome in the absence and presence of neuritic plaques (NPs).
Methods
We analyzed bulk brain RNA-seq data from two large brain-banks to evaluate expression of microglia- and astrocyte-predominant genes across APOE alleles. Follow on experiments in APOE knock-in mice were used to test the observation that APOE genotype is closely associated with selected inflammatory responses.
Results
In control subjects with no NPs, we identified a cluster of microglia-predominant genes that are up-regulated in APOEε4 carriers and down-regulated in APOEε2 carriers, relative to APOEε3 homozygotes. This microglia-APOE cluster is enriched in phagocytosis —including TREM2 and TYROBP— and pro-inflammatory genes. Many of these genes were also up-regulated in APOEε4 carriers versus APOEε3 homozygotes across CERAD stages independently of pathology, further confirming that this is a genotype effect, not just pathology-driven. Conversely, APOE-linked changes in astrocyte-predominant genes were modest and involved lipid metabolism and extracellular matrix. The APOE allele association was validated in APOE knock-in mice upon a lipopolysaccharide challenge, but not at baseline.
Conclusions
APOEε4 and APOEε2 have opposite effects on the microglial transcriptome in the human brain, independent of their known effects on Aβ plaques. APOE knock-in mice may recapitulate human APOE-linked glial gene expression patterns only upon microglia stimulation. Our study supports the relevance of the APOE-TREM2-TYROBP axis in microglial responses in normal aging.