Reactive Astrocytes as Drug Target in Alzheimer’s Disease

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.

Neurodegenerative Diseases – Is Metabolic Deficiency the Root Cause?

“…During aging, the CA3 region is hyperactivated, whereas the CA1 region showed a reduced firing rate (Kanak et al, 2013;Simkin et al, 2015;Oh et al, 2016). As we age, overexcitation of excitatory neurons leads to an excessive accumulation of glutamate in the synaptic cleft (Esposito et al, 2013;Assefa et al, 2018), which results in glutamate-induced toxicity. In aging, larger numbers of reactive astrocytes (A1) are observed in CA1 and striatal regions that, in turn, induce neuroinflammation and vulnerability in pyramidal neurons and MSNs of CA1 and striatal regions, respectively (Clarke et al, 2018).…”

The Potential Role of Astrocytes in Parkinson’s Disease (PD)

“…Moreover, astrocytes possess functional receptors for the uptake of neurotransmitters, and themselves respond to neurotransmitter stimulation by releasing transmitter molecules. In the CNS, the uptake of the neurotransmitter, glutamate, from the synaptic cleft by astrocytes occurs through Na + -dependent excitatory amino acid transporters (EAATs) [20,21]. In humans, EAATs provide the Na + -mediated driving force for glutamate uptake from the extracellular synaptic space [7,22].…”

“…This neuronal excitotoxicity is a known cause of neurodegenerative disorders [5]. The successive over-stimulation of glutamatergic N-methyl-D-asparate (NMDA) receptor induces numerous neurotoxic effects, such as intracellular Ca 2+ homeostasis dysfunction, increase nitric oxide (NO) and reactive oxygen species production, as well as reactive nitrogen radicals [3,21], resulting in mitochondrial dysfunction [3], the activation of proteases, and an increase in cytotoxic transcription factors [21]. Therefore, glutamate excitotoxicity can induce dopaminergic neuron death, movement disorder, cognitive impairment, and pathogenesis of PD [3].…”

Inhibition of Stat3 Phosphorylation Attenuates Impairments in Learning and Memory in 5XFAD Mice, an Animal Model of Alzheimer’s Disease

“…Since AD pathologies are the result of neuronal death, search for mechanisms and therapeutic approaches have been neurocentric until a recent time [27]. However, the importance of nonneuronal cells, such as astrocytes, is now largely accepted 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 therapeutics development [28,29].…”