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July 01-02, 2019 | Paris, France
Brain Disorders and Therapeutics
6th International Conference on
Journal of Brain and Neurology | Volume: 03
The Role of APOE in microglia regulation in Neurodegeneration
Oleg Butovsky
Center for Neurologic Diseases, USA
A lzheimer’s disease (AD) is the most prevalent
senile dementia affecting 4.5 million Americans.
Neuroinflammatory changes are prominent and may
significantly contribute to the pathologic process.
Mononuclear phagocytes (brain resident microglia and
recruited peripheral monocytes) accumulate around
amyloid plaque in AD brains. However, their exact cellular
identity, molecular and functional phenotypes, and
their protective or destructive roles in AD are not well
understood. This stems in part from the lack of a specific
molecular signatures for mononuclear phagocytes, cell
type-specific antibodies, and analytic tools for in situ
characterization. We recently identified a unique TGFβ-
dependent molecular signature of homeostatic (M0)- and
APOE-dependent neurodegenerative (MGnD)-microglia
in neurodegenerative mouse models including APP-PS1
mice and human AD. Mechanistically, the TREM2-APOE
pathway mediates a switch from M0- to MGnD-microglia
phenotype after phagocytosis of apoptotic neurons in a
cell-autonomous manner. TREM2 induces APOE signaling
which is a negative regulator of the transcription program
in M0-microglia.Transcription regulatory network analysis
identified direct effect of APOE on suppression of major
microglial homeostatic regulators including TGFβ signaling
and induction of disease-associated molecules which are
essential for pathogenicity in neuroinflammation. Specific
genetic ablation of Apoe and/orTrem2 inmicroglia restored
their homeostatic phenotype and genetic ablation of Apoe
or Trem2 in TAU (P301S) mice arrested neurodegeneration
and brain atrophy. Therefore, APOE plays an important role
in microglia phenotype regulation in neurodegenerative
conditions, and restoration of the homeostatic microglia
by targeting the APOE-signaling in microglia represents
a novel immunotherapeutic approach. Taken together,
our work identifies the TREM2-APOE pathway as a
major regulator of microglial functional phenotype in
neurodegenerative diseases and serves as a novel target
to restore homeostatic microglia. These advances have
major implications not only for understanding normal CNS
function, but have opened up new avenues to understand
the role of microglia in disease and most importantly
have created the opportunity for consideration of ways
in which microglial may be imaged and targeted for the
treatment of disease. Since APOE ε4 is the major risk factor
of the disease, we study the role of APOE ε4 in microglia
regulation by employing novel tools including new mouse
models and techniques to specifically target APOE in
order to restore microglia-mediated protein clearance and
brain function in animal models of tauopathies and AD.
I will present recent advances in understanding the new
molecular signature of homeostatic microglia, disease
associated microglia and how microglia are regulated in
health and disease.
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