The brains of patients who suffer from Alzheimer’s disease (AD) present with a significant immune response in the form of a pronounced inflammatory reaction. The mediators of this response are microglia, the immune cells (macrophages) of the central nervous system. A large body of evidence indicates that this immune reaction is a response to deposition of the fibrillar form of the amyloid-β peptide (fAβ), which is increased in Alzheimer’s brains and accumulates in plaques. Exposure to fAβ transforms quiescent microglia to the activated state and results in significant microglial recruitment to the site of fAβ deposition. We have demonstrated that the aged primate brain is selectively vulnerable to the toxic effects of fAβ. Injection of plaque-equivalent concentrations of fAβ (200 pg) into the cerebral cortex of the aged rhesus monkey produced significant neuronal loss and importantly, resulted in microglial recruitment and activation. The toxicity of Aβ was age-dependent, as injections of the same concentration of fAβ produced no neuronal loss or microglia activation in young rhesus monkeys. This effect was also species-dependent. Similar injections in the aged rat were without effect.
Microglia phagocytose fAβ following binding of the peptide to class A scavenger receptors (SR-A). Collaborative studies of the investigators established that exposure of quiescent murine microglia to fAβ in vitro also initiates a signaling cascade, involving the CD36 scavenger receptor (scavenger receptor 2B), which results in production of reactive oxygen species (ROS), chemokines, and potentially cytotoxic cytokines. Our preliminary observations indicate that activation of microglia is indeed responsible, at least in part, for fAβ toxicity in the aged rhesus brain. Treatment of aged rhesus with macrophage inhibitory factor resulted in a significant reduction in the number of activated microglia and in the size of the area of damage in fAβ injection sites.
Our observation that fAβ toxicity and microglia activation are seen in old but not young rhesus cortex combined with our finding that inhibition of microglia activation protects aged rhesus cortex against fAβ toxicity suggests that alterations in microglia function make a major contribution to fAβ toxicity in the aged primate and that microglia in the young primate cortex display a considerably different response to fAβ and hence little toxicity is seen in young primates. The proposed experiments will investigate age-related changes in the response to Aβ of microglia isolated from the human cortex. Given the recent evidence suggesting deleterious effects of the soluble oligomeric and protofibrillar Aβ, we shall also determine the effects of these conformations of Aβ on microglia.
Our recent preliminary evidence indicates that microglia from aged human brains display considerably reduced phagocytosis of Aβ when compared with microglia from young human brains. Aged microglia also displayed significantly reduced production of ROS in response to Aβ when compared with young microglia.
Based on the above observations, we hypothesize that microglia isolated from the aged human cerebral cortex will display significantly reduced phagocytosis of various conformations of Aβ when compared with microglia isolated from young brains. This is likely to give rise to greater accumulation of Aβ extracellularly, with the resultant chronic stimulation of CD36 receptor, activation of microglia and long term production of chemokines, cytokines, and ROS, causing neuronal degeneration. On the other hand, young microglia, despite the greater ability for production of ROS, efficiently phagocytose Aβ, likely reducing its extracellular levels, resulting in reduced stimulation of CD36, and only transient production of ROS, chemokines and cytokines.
