Alzheimer’s disease (AD) is the most common neurodegenerative disease of the elderly and its prevalence is increasing. The senile plaque is a pathological hallmark of AD and is composed of beta amyloid (Aβ), activated microglia, astyrocytes and degenerating neurons. Microglia are the principal innate immune cells of the brain. Microglia are recruited into the brain and accumulate in senile plaques. However, the exact role of microglia in the pathogenesis of AD has not been resolved. Microglia may play a neuroprotective role because of their ability to clear Aβ, but their subsequent activation and release of cytokines, chemokines, and neurotoxins may contribute to neurodegeneration.
The mechanism of microglial recruitment into normal or AD brains are not established. Published data suggest that in normal brains, microglia originate in the bone marrow, migrate into the blood and then populate the brain. A similar, but accelerated process may be occurring in AD. Chemokines are chemotactic cytokines that bind specific receptors on the surface of the leukocytes and mediate leukocytes accumulation at sites of inflammation. The exact role of chemokines and their receptors in the accumulation of microglia in normal or AD brains is not known. Published and preliminary data from the PI and co-investigator’s laboratories suggest that chemokine receptor CCR2, expressed on monocytes, microglia, astrocytes, and neurons, plays a critical role in microglial accumulation in the APP and PS1-APP mouse models of AD. In preliminary data, we demonstrate that CCR2 deficiency leads to impaired microglial accumulation in the brain, accelerated deposition of Aβ, and increased early mortality in the AD mice.
In this application, the PI, who has a long standing interest in the role of microglia in the innate immune response to Aβ and the identified scavenger receptors as key microglial receptors for Aβ, is collaborating with the co-investigator, an expert in the biology of chemokines, to investigate the role of CCR2 in the pathogenesis of AD and in the accumulation of microglia in AD. Using PS1-APP mice and CCR2-deficient mice and the technique of bone marrow transplantation, we will first confirm that the dramatic early effect we have observed in the CCR2-deficient APP and PS1-APP mice is the result of CCR2 deficiency only in hematopoietically derived cells (i.e. microglia and monocytes). By performing the bone marrow transplantation at later times, we will also be able to determine if CCR2 controls microglial accumulation throughout the course of the disease. If CCR2 controls microglial recruitment at later time points as well, we will then be able to use these techniques to dissect the exact role of microglia at various stages of AD.
In the second aim, we will determine at what point CCR2 controls the process of microglial recruitment from the bone marrow => blood => brain => senile plaque. We will determine whether CCR2 regulates the movement of microglial precursors from the bone marrow into the blood, or from the blood into the brain, or both. Finally, we will determine if CCR2 regulates the movement of microglia from the areas of the brain that do not have amyloid towards areas of amyloid accumulation. Specifically, we propose:
1. To determine whether CCR2 deficiency in bone marrow derived brain cells is sufficient to cause increased mortality and Aβ deposition in the PS1-APP mouse model of AD and if the effect of CCR2 deficiency persists throughout the course of the disease.
2. To determine whether CCR2 controls microglial recruitment from the bone marrow into the blood and/or from the blood into the brain of PS1-APP mice, and/or if CCR2 plays a role in the intracerebral migration of microglia into the senile plaque.
The proposed experiments will allow us to understand the role of CCR2 in accumulation of microglia in AD. Since our preliminary data suggests that CCR2 regulates microglial accumulation in AD, these experiments will also clarify the role of microglia in the pathogenesis and progression of AD.