Abstract
Alzheimer's disease is a neurodegenerative disease characterized by deposition of extracellular amyloid-β, intracellular neurofibrillary tangles, and loss of cortical neurons. However, the mechanism underlying neurodegeneration in Alzheimer's disease (AD) remains to be explored. Many of the researches on AD have been primarily focused on neuronal changes. Current research, however, broadens to give emphasis on the importance of nonneuronal cells, such as astrocytes. Astrocytes play fundamental roles in several cerebral functions and their dysfunctions promote neurodegeneration and, eventually, retraction of neuronal synapses, which leads to cognitive deficits found in AD. Astrocytes become reactive as a result of deposition of Aβ, which in turn have detrimental consequences, including decreased glutamate uptake due to reduced expression of uptake transporters, altered energy metabolism, altered ion homeostasis (K+ and Ca+), increased tonic inhibition, and increased release of cytokines and inflammatory mediators. In this review, recent insights on the involvement of, tonic inhibition, astrocytic glutamate transporters and aquaporin in the pathogenesis of Alzheimer's disease are provided. Compounds which increase expression of GLT1 have showed efficacy for AD in preclinical studies. Tonic inhibition mediated by GABA could also be a promising target and drugs that block the GABA synthesizing enzyme, MAO-B, have shown efficacy. However, there are contradictory evidences on the role of AQP4 in AD.
Highlights
Alzheimer’s disease is a neurodegenerative disease clinically characterized by progressive deterioration of memory
The importance of nonneuronal cells, such as astrocytes, is largely acknowledged and opened new research avenues that aim at better understanding of the pathology of the disease as well as characterizing new cellular and molecular targets for drug development [10, 11]
Astrocytes are involved in uptake of glutamate from synaptic space by excitatory amino acid transporter including GLT1
Summary
Alzheimer’s disease is a neurodegenerative disease clinically characterized by progressive deterioration of memory. Several hypotheses have been proposed to address the pathological lesions and neuronal cytopathology of the disease Of these hypotheses, the amyloid metabolic cascade and the intracellular neurofibrillary tangles are considered the most important hypotheses [5, 6]. Many pharmacological treatments targeting at these and other hypotheses have been unsuccessful to delay the progress of the disease significantly. This explains that no single theory alone is sufficient to explain the biochemical and pathological abnormalities of AD, which is believed to involve a multitude of cellular and biochemical changes [6, 7]. The purpose of this review is to explore the role of reactive astrocytes in AD
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