Dissecting Alzheimer's Disease Risk Genes: Insights from Immune Genetic Perturbations
You are cordially invited to a special seminar
of the Department of Physiology and Pharmacology
Department of Pathology
Department of Clinical Microbiology and Immunology
By:
Neta Rosenzweig, PhD
Dissecting Alzheimer's Disease Risk Genes:
Insights from Immune Genetic Perturbations
Objectives: APOE4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). The role of human APOE variants in AD has been studied extensively in the regulation of brain cells but not in peripheral immunity. APOE is also expressed in neutrophils and controls their activation. Neutrophils play a negative role in AD mice via the induction of neutrophil degranulation and extracellular traps. Here we aimed to dissect the impact of APOE4 on neutrophil phenotypes and functions in the transition from unimpaired cognition to mild cognitive impairment (MCI) and AD.
Methods: RNAseq and pathway analysis of sorted neutrophils isolated from MCI, AD and aged-matched healthy control (HC) subjects identified APOE4 sex-dependent induction of neutrophil degranulation in HC females associated with upregulation of immunosuppressive cytokines. Using multicolour flow cytometry, we extended these findings and identified a novel immunosuppressive neutrophil subset that is expanded in HC female APOE4 carriers and is enriched during the transition to MCI/AD.
Results: APOE4 neutrophils accumulated in the brains of AD mice and in AD patients, associated with microglia at sites of plaque pathology. Furthermore, we show impaired induction of disease-associated microglia (DAM/MGnD) signature in AD brains of APOE4 carriers. Utilizing Ly6g-CRE mice crossed to APOE-KI(E3 and E4)fl/fl:APP/PS1 mice, we identified a cell-intrinsic role of APOE3 in controlling neutrophil aging and degranulation, which is exacerbated in APOE4-KI neutrophils and reduced in APOE4-KO neutrophils. Deletion of APOE4 in neutrophils suppressed their activation and reduced their recruitment to the brains of APP/PS1 mice. RNAseq analysis showed increased proportion of MGnD in APP/PS1APOE4NTKO mice, associated with reduced plaque pathology.
Conclusions: Taken together, these findings identify a cell-intrinsic role of APOE4 in the induction of immunosuppressive neutrophils recruited to the brain, which may provide new molecular targets to modulate and restore functional microglial activation to limit AD progression.
The Seminar will take place on Wednesday, December 31, 10:15-11:00
At the Faculty of Medical & Health Sciences, Room 215
