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Published on: November 9, 2018
Mechanisms of microglia accumulation in Alzheimer's disease: therapeutic implications
Joseph El Khoury1, Andrew D Luster
1Division of Rheumatology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. jelkhoury@partners.org
Abstract:
In Alzheimer's disease (AD), and other conditions affecting integrity of the blood-brain barrier, microglia can originate in the bone marrow, migrate into the blood and enter the brain in a chemokine-dependent manner. CCR2, a chemokine receptor that controls mononuclear phagocyte infiltration into the brain in multiple sclerosis, bacterial meningitis and neuropathic pain, also regulates microglia accumulation in mouse models of AD. CCR2 deficiency leads to lower microglia accumulation and higher brain beta-amyloid (Abeta) levels, indicating that early microglial accumulation promotes Abeta clearance. In support of this protective role, enhancing microglia accumulation delays progression of AD. AD mice that constitutively express interleukin-1 in the brain, or that are deficient in peripheral mononuclear phagocyte transforming growth factor-beta signaling, have increased microglia accumulation around beta-amyloid plaques and reduced AD-like pathology. Regulating microglia recruitment into the brain is a novel therapeutic strategy to delay or stop progression of AD. Here, we review the role of microglia in AD and the mechanisms of their accumulation and discuss implications for AD therapy.
Insights
Microglia recruitment into the brain is crucial for clearing beta-amyloid plaques in Alzheimer's disease (AD). Enhancing this process may offer a novel therapeutic strategy to slow AD progression.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Microglia, the brain's immune cells, play a role in Alzheimer's disease (AD) pathology.
- Blood-brain barrier integrity is compromised in AD, allowing peripheral cells to enter the brain.
- Chemokine receptors, like CCR2, regulate immune cell migration into the central nervous system.
Purpose of the Study:
- To review the role of microglia in Alzheimer's disease.
- To explore the mechanisms of microglia accumulation in the brain.
- To discuss the therapeutic implications of modulating microglia recruitment for AD.
Main Methods:
- Review of existing literature on microglia, CCR2, and Alzheimer's disease.
- Analysis of studies using mouse models of AD.
- Examination of the relationship between microglia accumulation and beta-amyloid pathology.
Main Results:
- CCR2 receptor signaling regulates microglia accumulation in AD mouse models.
- CCR2 deficiency is associated with reduced microglia accumulation and increased beta-amyloid levels.
- Enhanced microglia accumulation correlates with delayed AD progression and reduced pathology.
Conclusions:
- Microglia recruitment into the brain is a promising therapeutic target for Alzheimer's disease.
- Modulating chemokine pathways, such as CCR2, could enhance Abeta clearance.
- Targeting microglia accumulation may offer a novel strategy to delay or halt AD progression.
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