Deleterious Alteration of Glia in the Brain of Alzheimer’s Disease

Abstract

The deterioration of neurons in Alzheimer’s disease (AD) arises from genetic, immunologic, and cellular factors inside the cortex. The traditional consensus of the amyloid-beta (Aβ) paradigm as a singular cause of AD has been under revision, with the accumulation of exploding neurobiological evidence. Among the multifaceted casualties of AD, the involvement of glia gains significance for its dynamic contribution to neurons, either in a neuroprotective or neurotoxic fashion. Basically, microglia and astrocytes contribute to neuronal sustainability by releasing neuroprotective cytokines, maintaining an adequate amount of glutamate in the synapse, and pruning excessive synaptic terminals. Such beneficial effects divert to the other detrimental cascade in chronic neuroinflammatory conditions. In this change, there are new discoveries of specific cytokines, microRNAs, and complementary factors. Previously unknown mechanisms of ion channels such as Kv1.3, Kir2.1, and HCN are also elucidated in the activation of microglia. The activation of glia is responsible for the excitotoxicity through the overflow of glutamate transmitter via mGluRs expressed on the membrane, which can lead to synaptic malfunction and engulfment. The communication between microglia and astrocytes is mediated through exosomes as well as cytokines, where numerous pieces of genetic information are transferred in the form of microRNAs. The new findings tell us that the neuronal environment in the AD condition is a far more complicated and dynamically interacting space. The identification of each molecule in the milieu and cellular communication would contribute to a better understanding of AD in the neurobiological perspective, consequently suggesting a possible therapeutic clue.

When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer’s and Huntington’s Disease

“…Since astrocytes contribute to Aβ catabolism, astrocyte dysfunction could contribute to the pathogenic accumulation of Aβ [ 26 ]. Additionally, while astrocytes and microglia ultimately cause neuroinflammation, under normal circumstances these cells secrete cytokines that support the survival and functioning of neurons, a function which is lost when these cell types become functionally compromised [ 26 , 27 ]. Although less studied than astrocytes and microglia, emerging evidence suggests that impaired functioning of oligodendrocytes and their progenitor cells (which remain through adulthood) may also play a causal role in AD.…”

The Potential Role of Protein Kinase R as a Regulator of Age-Related Neurodegeneration

“…Histological studies of brains from AD patients and AD animal models show a strong colocalization of reactive glial cells with senile plaques and neurofibrillary tangles ( Parachikova et al, 2007 ; Hickman et al, 2008 ; Lopez-Gonzalez et al, 2015 ). The inflammatory cascade mechanism during AD associated with Aβ toxicity has been largely reviewed before ( Bruni et al, 2020 ; Kim et al, 2020 ; Merlo et al, 2020 ; Webers et al, 2020 ). In brief, microglia and astrocyte activation participates in Aβ clearance on AD progression’s earlier steps ( Ries and Sastre, 2016 ).…”

Implications of exosomes derived from cholesterol-accumulated astrocytes in Alzheimer's disease pathology

“…Considering the multifaceted roles of different subtype astrocytes in various experimental conditions ( Li et al, 2019 ; Liddelow and Barres, 2017 ), it is possible that astrocytes at early stages of AD may serve a protective role by relieving neurons from accumulated toxic materials. However, as the disease advances with compromised EL/autophagic-lysosomal system, astrocytic exosomes may act not only to propagate disease pathology but also to trigger dysfunction/degeneration of neurons in the affected brain regions ( Kim et al, 2020 ; Upadhya et al, 2020 ; Venturini et al, 2019 ). Thus, characterizing the spatiotemporal function of exosomes derived from astrocytes from experiments relevant to disease pathology may provide a better understanding about the role of astrocytes in AD pathogenesis.…”