Neta Rosenzweig (United States of America)
Brigham and Women's Hospital, Harvard Medical School
Neurology
For over 10 years I have been involved in studying how immune cells and associated molecules affect brain function under physiological and neurodegenerative conditions, focusing on Alzheimer’s disease (AD). During my PhD studies, we identified regulatory T cells-mediated systemic immunosuppression as negative player in murine models of AD, and targeting these cells using genetic tools or pharmacological inhibition, led to mitigation of disease pathology and reversal of cognitive decline. Later as a postdoc, I continued studying the interactions between the CNS and peripheral immune cells and their impact on AD, focusing on APOE4, the strongest genetic risk factor for AD, as a regulator of this crosstalk.

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 Conference Calendar

APOE4 IMPAIRS MICROGLIA RESPONSE TO NEURODEGENERATION IN ALZHEIMER’S DISEASE

Session Name
0850 - APOE MECHANISMS AND TREATMENT STRATEGIES 2 (ID 136)
Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
05:15 PM - 07:15 PM
Room
ONSITE: 114
Lecture Time
05:45 PM - 06:00 PM
Presenter

Abstract

Aims

APOE4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). We previously identified that APOE signaling governs the transcriptional regulation from homeostatic to neurodegenerative microglia (MGnD). However, the underlying mechanism for APOE4-mediated microglial dysregulation and its contribution to increased risk for developing AD, is unknown.

Methods

Here we aimed to dissect the impact of microglial APOE4 on AD pathology, 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. Moreover, APOE4-KI mice challenged with labeled apoptotic neurons, failed to respond to acute neurodegeneration, depicted by reduced numbers of phagocytic MGnD-microglia at injection site compared with APOE3-KI mice. Here we show that conditional genetic deletion of APOE4 in microglia resulted in increased numbers of MGnD-microglia in response to acute neurodegeneration and in APP/PS1 mice. scRNAseq analysis showed increased proportion of MGnD-microglia in APP/PS1:APOE4 conditional KO mice, associated with reduced plaque pathology and increased astrocytic recruitment towards plaques. Furthermore, we show impaired induction of MGnD signature in AD brains of APOE4 carriers.

Conclusions

Our findings show that APOE4 is a negative regulator of MGnD-microglia in AD, and that its genetic deletion restores the induction of MGnD signature associated with reduction in plaque pathology. Taken together, these findings identify a cell-intrinsic role of APOE4 in the induction of dysfunctional MGnD microglia and their impaired response to neurodegeneration, which may provide new molecular targets to modulate and restore functional microglia in AD.

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