Targeting Inflammatory Microglia in Alzheimer's Disease
It is becoming increasingly clear that chronic inflammation is important in the major neurodegenerative conditions, such as Alzheimer's disease. Animal studies suggest that a sizable portion of that inflammation is caused by the activities of activated and senescent microglia, innate immune cells of the brain. Both the use of CSF1R inhibitors (such as pexidartinib) to clear all microglia and the use of senolytics (such as the dasatinib and quercetin combination) to selectively destroy senescent microglia have shown benefits in animal models of neurodegeneration and brain injury. Interestingly, dasatinib is both a senolytic and a CSF1R inhibitor. Since these drugs are readily available and already used in human medicine, it would be quite feasible to run clinical trials, given the funding and the will to do so.
Alzheimer's disease (AD) is a common, progressive, and devastating neurodegenerative disorder that mainly affects the elderly. Microglial dysregulation, amyloid-beta (Aβ) plaques, and intracellular neurofibrillary tangles play crucial roles in the pathogenesis of AD. In the brain, microglia play roles as immune cells to provide protection against virus injuries and diseases. They have significant contributions in the development of the brain, cognition, homeostasis of the brain, and plasticity. Multiple studies have confirmed that uncontrolled microglial function can result in impaired microglial mitophagy, induced Aβ accumulation and tau pathology, and a chronic neuroinflammatory environment.
In the brain, most of the genes that are associated with AD risk are highly expressed by microglia. Although it was initially regarded that microglia reaction is incidental and induced by dystrophic neurites and Aβ plaques, nonetheless, it has been reported by genome-wide association studies that most of the risk loci for AD are located in genes that are occasionally uniquely and highly expressed in microglia. This finding further suggests that microglia play significant roles in early AD stages and they be targeted for the development of novel therapeutics.
In this review, we have summarized the molecular pathogenesis of AD, microglial activities in the adult brain, the role of microglia in the aging brain, and the role of microglia in AD. We have also particularly focused on the significance of targeting microglia for the treatment of AD.