آستروسیت ها واکنشگر از نورون پشتیبانی کمتری می کنند: مفاهیم برای بیماری آلزایمر

Astrocytes become activated in Alzheimer's disease (AD), contributing to and reinforcing an inflammatory cascade. It is proposed that by transforming from a basal to a reactive state, astrocytes neglect their neurosupportive functions, thus rendering neurons vulnerable to excitotoxicity and oxidative stress. This review considers 3 important astrocytic functions, that when disrupted, can affect neuronal metabolism. These are the uptake of glucose and release of lactate; the uptake of glutamate and release of glutamine; and the uptake of glutathione precursors and release of glutathione. Conditions under which these functions can be manipulated in vitro, as well as examples of possible loss of astrocytic function in AD, are discussed. It is proposed that the targeting of astrocytes with pharmacological agents that are specifically designed to return astrocytes to a quiescent phenotype could represent a fruitful new angle for the therapeutic treatment of AD and other neurodegenerative disorders.

Astrocytes serve an array of important functions, including the regulation of extracellular ion concentrations, synaptic remodeling (addition and removal of synapses), and the maintenance of protective barriers, such as the glia limitans, glial scars, and blood-brain barrier. The ensheathment of blood vessels and synapses by astrocytic processes enables these cells to monitor the extracellular ionic environment and to mediate the transfer of metabolites between cerebral blood vessels and neurons. Three interrelated astrocyte-neuronal interactions, discussed herein, are glucose uptake and lactate release, glutamate recycling, and the synthesis of glutathione.

Twenty-one years ago Hertz (1989) advanced the radical proposal that AD may constitute ‘a cruel demonstration by Nature of the crucial importance of functional and metabolic interactions between neurons and astrocytes for normal brain function’. The present review has shown that a considerable body of evidence has accumulated in support of Hertz's proposal. Furthermore, the reason for the breakdown in this symbiosis is becoming clear. It has become evident that the transformation of astrocytes from a basal to a reactive state, in response to inflammation or oxidative stress, can trigger a change in their metabolic phenotype. This change in phenotype appears to provide a basis for many of the metabolic perturbations that occur in AD, and which contribute to the pathogenesis and progression of the disease. The adoption of a reactive metabolic phenotype is likely to assist the brain to survive in instances of local acute injury, but it could become counterproductive if the response is sustained and widespread. When astrocytes adopt a reactive phenotype, their efforts are redirected toward defensive and repair tasks at the expense of providing adequate metabolic support to neurons. Viewed from this perspective, the targeting of astrocytes with pharmacological agents that are specifically designed to return astrocytes to a quiescent phenotype could represent a fruitful new angle for the therapeutic treatment of AD and other neurodegenerative disorders. (Fig. 2).