Abstract
Alzheimer disease (AD) is a frequent and devastating neurodegenerative disease in humans, but still no curative treatment has been developed. Although many explicative theories have been proposed, precise pathophysiological mechanisms are unknown. Due to the importance of astrocytes in brain homeostasis they have become interesting targets for the study of AD. Changes in astrocyte function have been observed in brains from individuals with AD, as well as in AD in vitro and in vivo animal models. The presence of amyloid beta (Aβ) has been shown to disrupt gliotransmission, neurotransmitter uptake, and alter calcium signaling in astrocytes. Furthermore, astrocytes express apolipoprotein E and are involved in the production, degradation and removal of Aβ. As well, changes in astrocytes that precede other pathological characteristics observed in AD, point to an early contribution of astroglia in this disease. Astrocytes participate in the inflammatory/immune responses of the central nervous system. The presence of Aβ activates different cell receptors and intracellular signaling pathways, mainly the advanced glycation end products receptor/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, responsible for the transcription of pro-inflammatory cytokines and chemokines in astrocytes. The release of these pro-inflammatory agents may induce cellular damage or even stimulate the production of Aβ in astrocytes. Additionally, Aβ induces the appearance of oxidative stress (OS) and production of reactive oxygen species and reactive nitrogen species in astrocytes, affecting among others, intracellular calcium levels, NADPH oxidase (NOX), NF-κB signaling, glutamate uptake (increasing the risk of excitotoxicity) and mitochondrial function. Excessive neuroinflammation and OS are observed in AD, and astrocytes seem to be involved in both. The Aβ/NF-κB interaction in astrocytes may play a central role in these inflammatory and OS changes present in AD. In this paper, we also discuss therapeutic measures highlighting the importance of astrocytes in AD pathology. Several new therapeutic approaches involving phenols (curcumin), phytoestrogens (genistein), neuroesteroids and other natural phytochemicals have been explored in astrocytes, obtaining some promising results regarding cognitive improvements and attenuation of neuroinflammation. Novel strategies comprising astrocytes and aimed to reduce OS in AD have also been proposed. These include estrogen receptor agonists (pelargonidin), Bambusae concretio Salicea, Monascin, and various antioxidatives such as resveratrol, tocotrienol, anthocyanins, and epicatechin, showing beneficial effects in AD models.
Highlights
The loss of cognitive abilities induced by the development of dementia represents one of the main pathological burdens in humans, critically interfering with social and occupational activities
Cytokines seem to act on the 5 -untranslated region (5 -UTR) of the amyloid precursor protein (APP) gene in astrocytes (Lahiri et al, 2003). It seems that the presence of amyloid beta (Aβ) is able to induce the production and release of pro-inflammatory cytokines and chemokines from astrocytes, which could as well act in an autocrine manner to further induce the production of Aβ from astrocytes and possibly other cells. These results suggest that inflammation may be present at early stages of the disease or even that inflammation may be responsible for the appearance of pathological Aβ production and accumulation
Another possible factor contributing to the presence of neuroinflammation is the blood–brain barrier (BBB), as in Alzheimer’s disease (AD), it has been reported that the BBB occasionally loses its integrity (Chakraborty et al, 2017)
Summary
The loss of cognitive abilities induced by the development of dementia represents one of the main pathological burdens in humans, critically interfering with social and occupational activities. Alterations in the cleaving process of APP produce abnormal lengthy species of the Aβ peptide which are deleterious to the brain cellular environment These Aβ species have been reported to exhibit different profiles of toxicity, and among them, the soluble forms seem to be more neurotoxic than the fibrillary (aggregated) forms. Astrocytes are key for the maintenance of homeostatic balance and participate in processes such as neurotransmitter uptake and recycling, gliotransmitter release, neuroenergetics, inflammation, modulation of synaptic activity, ionic balance, and maintenance of BBB, among others (Magistretti and Allaman, 2015; Iglesias et al, 2017; Vasile et al, 2017) Due to this wide array of functional properties, astrocytes have become interesting targets for the study and treatment of numerous brain pathologies. The interruption of astrocyte’s functions and in glia transmission, may result in different neuropsychiatric disorders (Rajkowska et al, 1999; Cohen-Gadol et al, 2004; Fellin et al, 2004; Webster et al, 2005), as well as neurodegenerative diseases, including AD (Forman et al, 2005; Halassa et al, 2007)
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