Astrocytes in Neurodegenerative Diseases: A Perspective from Tauopathy and α-Synucleinopathy

Abstract

Neurodegenerative diseases are aging-associated chronic pathological conditions affecting primarily neurons in humans. Inclusion bodies containing misfolded proteins have emerged as a common pathologic feature for these diseases. In many cases, misfolded proteins produced by a neuron can be transmitted to another neuron or a non-neuronal cell, leading to the propagation of disease-associated pathology. While undergoing intercellular transmission, misfolded proteins released from donor cells can often change the physiological state of recipient cells. Accumulating evidence suggests that astrocytes are highly sensitive to neuron-originated proteotoxic insults, which convert them into an active inflammatory state. Conversely, activated astrocytes can release a plethora of factors to impact neuronal functions. This review summarizes our current understanding of the complex molecular interplays between astrocyte and neuron, emphasizing on Tau and α-synuclein (α-syn), the disease-driving proteins for Alzheimer's and Parkinson's diseases, respectively.

Keywords: Alzheimer’s disease; Parkinson’s disease; Tau; astrocyte; cell-to-cell transmission; neurodegenerative disease; prion; tauopathy; α-synuclein; α-synucleinopathy.

Figure 1

A dual role of microglia and astrocytes in neuronal growth and neurodegenerative diseases. Accumulating evidence suggests that the activation of microglia and astrocytes may be a double-edged sword. Under healthy conditions, microglia and astrocytes engulf neuron-derived misfolded proteins such as Tau and α-syn to promote protein homeostasis in the brain micro-environment. Astrocytes can also provide other supportive functions including axonal guidance and synaptic support. However, when these cells are overactivated by toxic factors (e.g., LPS or excess amount of extracellular Tau or α-syn), they release pro-inflammatory cytokines and chemokines to disrupt neuronal integrity. Reactive microglia can also cross-activate astrocytes by releasing cytokines such as TNFα, IL1-α and C1q. Conversely, astrocytes release complement C3, which can act on both microglia and neurons to further enhance neuroinflammation. Image created in BioRender.com.