Oleg Butovsky (United States of America)
Ann Romeny Center for Neurologic Diseases
Brigham and Women's Hospital, Harvard Medical School
Dr. Butovsky’s major scientific interest is to understand the biology of microglia and peripheral innate immunity in homeostasis and neurodegenerative conditions. Dr. Butovsky’s lab has made seminal discoveries including the identification of the TGFβ-dependent homeostatic microglia and the second major microglia phenotype, neurodegenerative MGnD-microglia which is regulated by TREM2-APOE pathway. These series of investigations led to the generation of novel tools to study microglial biology in health and disease and prompted to investigate further the role of central and peripheral innate immunity in neurodegenerative diseases. Current lab directions include: 1) investigation of environmental cues, early life stress, and the genetic factors APOE4 associated with microglial dysfunction in AD; 2) developing microglia-specific therapeutic delivery strategies; 3) developing a novel transgenic mouse model to target MGnD-microglia subset; 4) reprogramming human blood monocytes into microglia-like cells to restore microglial functions; 5) modulating and restoring functional crosstalk between microglia-innate and microglia-adaptive immunity in neuroinflammation; 6) identification of immune cell-based biomarkers predictive of AD progression; and 7) developing PET-based microglial biomarkers.

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 Conference Calendar

APOE4-MEDIATED MICROGLIAL REGULATION HAS AN OPPOSITE EFFECT IN ALZHEIMER’S DISEASE AND GLAUCOMA

Session Name
0740 - APOE: MECHANISMS AND TREATMENT STRATEGIES 1 (ID 37)
Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
02:45 PM - 04:45 PM
Room
ONSITE: 112
Lecture Time
04:00 PM - 04:15 PM
Presenter

Abstract

Aims

APOE4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). However, the molecular mechanism associated with its deleterious effect in AD and its protective role in glaucoma, is unknown.

Methods

Here we aimed to dissect the impact of microglial APOE4 on AD pathology and glaucoma models, using CX3CR1-CREERT2 mice crossed to APOE-KI(E3 and E4)fl/fl:APP/PS1.

Results

We identified reduced numbers of Clec7a+ MGnD-microglia per plaque in APP/PS1:APOE4-KI mice, despite their increased plaque load, compared with APP/PS1:APOE3-KI mice. APOE4 microglia accumulate lipids and represent a dysfunctional metabolic state. Conditional genetic deletion of APOE4 in microglia resulted in increased numbers of MGnD-microglia per plaque in APP/PS1 mice. scRNAseq analysis showed increased proportion of MGnD-microglia in APP/PS1:APOE4 conditional KO mice, associated with reduced plaque pathology. Furthermore, we show impaired induction of MGnD signature in AD brains of APOE4 carriers. We observed a similar microglial phenotype in both mouse model and human glaucoma. However, this microglial signature showed impaired MGnD response in glaucoma mice expressing APOE4, which was associated with protection of retinal ganglion cells (RGC), despite elevated intraocular pressure. Importantly, genetic and pharmacologic targeting of LGASL3 ameliorated RGC degeneration, and LGALS3 expression was attenuated in human APOE4 glaucoma samples.

Conclusions

We show that APOE4 is a negative regulator of MGnD in AD, and that its genetic deletion restores an MGnD signature and reduce plaque pathology. Taken together, these findings identify a beneficial role of MGnD in AD and their detrimental role in glaucoma, which may provide new molecular targets to modulate and restore functional microglia in AD.

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