Astrocyte alterations in neurodegenerative pathologies and their modeling in human induced pluripotent stem cell platforms

Abstract

Astrocytes are the most abundant cell type in the brain. They were long considered only as passive support for neuronal cells. However, recent data have revealed many active roles for these cells both in maintenance of the normal physiological homeostasis in the brain as well as in neurodegeneration and disease. Moreover, human astrocytes have been found to be much more complex than their rodent counterparts, and to date, astrocytes are known to actively participate in a multitude of processes such as neurotransmitter uptake and recycling, gliotransmitter release, neuroenergetics, inflammation, modulation of synaptic activity, ionic balance, maintenance of the blood-brain barrier, and many other crucial functions of the brain. This review focuses on the role of astrocytes in human neurodegenerative disease and the potential of the novel stem cell-based platforms in modeling astrocytic functions in health and in disease.

Keywords: Alzheimer’s disease; Amyotrophic lateral sclerosis; Astrocytes; Neurodegeneration; Parkinson’s disease.

Fig. 1

a Astrocytes and the pre- and post-synaptic endings of neurons form the tripartite synapse. Astrocytes clear neurotransmitters and secrete gliotransmitters, e.g., GABA, glutamate, d-serine, and ATP [5, 6]. In addition, they provide structural support and produce many cell adhesion and extracellular matrix-related molecules required for proper synaptic function. In AD, APOE4 astrocytes have decreased rate of synapse pruning and turnover in the brain [18]. In AD expression of GABA, the inhibitory gliotransmitter, in reactive astrocytes, is increased, whereas reduced other gliotransmitter release, especially ATP [–24]. b Blood–brain barrier. Astrocytic perivascular endfeet express water channel aquaporin-4 (AQP4) and the ATP-sensitive inward rectifier potassium channel Kir4.1, and transporter proteins such as glucose transporter-1 and P-glycoprotein [37]. Astrocytes support the BBB through the release of several growth factors including vascular endothelial growth factor (VEGF), glial cell line-derived neurotrophic factor (GDNF), basic fibroblast growth factor (bFGF), and angiopoietin 1 (ANG-1) [41]. Astrocytes communicate with each other through gap junction proteins mainly connexin (Cx) 43 and Cx 30. Astrocytic APOE4 promotes BBB disruption in AD. The release of pro-inflammatory cytokines including IL-6, IL-1B, and TNF-A in PD increase neuronal death and rearrange TJ protein expression on ECs. Astrocyte ability to maintain water and potassium homeostasis is reduced in ALS due to increased expression of AQP4 and reduced Kir4.1 [75]. c Astrocytes provide metabolic support to the neurons and maintain neurotransmitter homeostasis, actively responding on neuronal signals [86]. In neurodegenerative disease, these functions are compromised. Astrocytes exposed to amyloid peptides alter glucose uptake and its downstream metabolism in parallel with increased hydroperoxide and glutathione release. AD impacts astrocytic metabolism causing increased glutamate and ATP release, what in turn results in stimulation of microglial activation and neuronal vulnerability [101]. Astrocytic expression of PD-related A53T mutant alpha-synuclein results in down regulation of glutamate transporters and wide-spread gliosis [108]. In ALS, chronic activation of the α2-Na/K ATPase/α-adducin complex in astrocytes has been demonstrated, resulting in biased energy metabolism and acquisition of pro-inflammatory phenotype [131]. d Astrocytes mediate inflammatory effects in neurodegeneration. Astrocytic activity is affected by plethora of cytokines; INF-γ, IL-1β, IL-6, and TNF-α lead to classical activation, whereas IL-10, IL-4, and IL-13 induce alternative activation with decreased ROS and NO production alleviating inflammation [139]. In addition, astrocytes release factors affecting their inflammatory environment. Different cytokine levels are known to be affected in neurodegenerative disorders. In AD, astrocyte associated inflammation has been linked to IL-1β, IL-6, TNF-α, and TGF-β leading to activation of microglial cells [145]. Whereas, levels of IL-1β, TGF-β, and IFNs have been demonstrated to be elevated in post-mortem tissues of ALS patients [161]. Finally, in PD, levels of IL-1β, TNF-α, and IFN- γ are shown to be affected [153, 154]. e Astrocytes and oxidative stress in neurodegenerative diseases. In normal physiological conditions, astrocytes are glycolytic, whereas neurons are more oxidative and produce much more ROS than astrocytes do; however, increased ROS production by astrocytes has been reported in both AD and ALS [187, 196]. On the other hand, astrocytes have much higher antioxidant capacity than neurons and express higher levels of Nrf2, catalase and GSH, than neurons. Oxidative stress induces GSH release from astrocytes, which is degraded, and the cysteine-rich degradation products are taken up by neurons and used for neuronal GSH synthesis. [–200]