Alzheimer'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 identified that a specific microRNA, miR-155, plays a key role in pro-inflammatory activation of microglia, whereas the TREM2/apolipoprotein E (APOE) axis plays a central role to suppress homeostatic M0 microglia. This may lead to impaired amyloid-? peptide clearance and acceleration of neurodegeneration. Thus, the balance between TREM2 and MERTK expression determines the microglial inflammatory response to apoptotic cells. Restoration of the homeostatic microglia by targeting the specific MERTK pathway represents a novel immunotherapeutic approach. Our preliminary data demonstrate that these novel molecular targets (miR-155, APOE, TREM2 and MERTK) are highly connected biological molecular regulators of microglial phenotypes and thus we will investigate each of these targets to determine their roles in AD. We hypothesize that danger signals (dead neurons and amyloid-? peptides) alter functional phenotype of innate immune cells from the homeostatic (M0) to newly discovered neurodegenerative (MGnD) phenotype. We will address our hypothesis in the following aims:
Aim 1 : Targeting Trem2-induced Apoe/miR155 pathway to restore M0-homeostatic microglia in AD mouse models. We will specifically delete miR-155, Apoe and Trem2 in microglia of AD mouse models.
Aim 2 : Restoration of M0-homeostatic microglia via Mertk pathway in humanized APOE4 and AD mice. We will specifically over-express Mertk in microglia of APOE4 humanized mice and AD mouse models. We will validate our findings by investigating AD brains from prodromal to advanced stages. The goal of our investigations is to define new molecular mechanisms of immune and inflammatory processes that contribute to the development and progression of AD, which in turn will provide a basis for new approaches for immune based therapy of the disease.

Public Health Relevance

This application will elucidate the novel functions of molecules expressed in brain macrophage (microglia) as potential therapeutic targets of Alzheimer's disease (AD). We will focus on a specific microRNA, miR-155, and genes (TREM2 and APOE) as molecular targets to restore microglia-mediated protein clearance and brain function in animal models of AD. Since APOE4 is the major risk factor of the disease, we will study the role of APOE4 in microglial dysfunction by employing novel tools including new mouse models and laser capture techniques to specifically investigate the microglial gene signature from postmortem human brain tissue.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG054672-02
Application #
9538138
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Wise, Bradley C
Project Start
2017-08-15
Project End
2022-04-30
Budget Start
2018-06-01
Budget End
2019-04-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
DeLeo, Annina M; Ikezu, Tsuneya (2018) Extracellular Vesicle Biology in Alzheimer's Disease and Related Tauopathy. J Neuroimmune Pharmacol 13:292-308
Shi, Yang; Yamada, Kaoru; Liddelow, Shane Antony et al. (2017) ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549:523-527
Clayton, Kevin A; Van Enoo, Alicia A; Ikezu, Tsuneya (2017) Alzheimer's Disease: The Role of Microglia in Brain Homeostasis and Proteopathy. Front Neurosci 11:680
Krasemann, Susanne; Madore, Charlotte; Cialic, Ron et al. (2017) The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity 47:566-581.e9
Butovsky, Oleg; Jedrychowski, Mark P; Moore, Craig S et al. (2014) Identification of a unique TGF-?-dependent molecular and functional signature in microglia. Nat Neurosci 17:131-43