Alzheimer’s disease and age-dependent impair of microglia

Alzheimer’s disease (AD) is a severe neurodegenerative disease. It is characterized by senile plaques, neurofibrillary tangles and neuroinflammation. Senile plaques are extracellular deposits of β-amyloid (Aβ) and neurofibrillary tangles are intracellular aggregates of hyperphosphorylated tau. Although the mechanism is unknown, it is believed that these characteristics lead to neurodegeneration. Despite many years of research, there is still no cure available for this disease. The current treatments have limited efficacy and are also associated with many side-effects. Epidemiological studies suggested that anti-inflammatory drugs could have a protective role for AD development. These findings suggested that neuroinflammation plays an important role in AD pathology, but the mechanism is unknown. Neuroinflammation is mainly associated with microglial activation. In AD microglia are activated in response to Aβ exposure. Activated microglia try to clear Aβ by phagocytose and degrading enzymes. Besides the neuroprotective properties, activated microglia also have neurotoxic effects. Activated microglia release pro-inflammatory cytokines, complement proteins, ROS and NO, all of which can contribute to neurodegeneration when the microglial activation is persistent. Aging is the main risk for AD and this might be due to microglial senescence. Microglial senescence is characterized by morphological and functional changes. Aging microglia are becoming less sufficient in Aβ clearance and hyperactive in their pro-inflammatory cytokine release. Therefore, aged microglia decrease their protective and increase their harmful properties. Although this microglial senescence is a characteristic of normal brain aging, it is exacerbated in AD. This increased microglial function impairment is able to enhance the severity and chronicity of AD pathology. Studies showed that Aβ, which is increased in AD, is able to deteriorate and accelerate microglial senescence. Thus age-dependent microglial impairment is probably not the cause of AD, but it can play a major role in the progression of this disease. Inhibition of microglial senescence could thereby serve as a new target for AD treatment.