Good, bad, and neglectful: Astrocyte changes in neurodegenerative disease

Abstract

Astrocytes play key roles in CNS development as well as well as neuro-supportive roles in the mature brain including ionic, bioenergetic and redox homeostasis. Astrocytes undergo rapid changes following acute CNS insults such as stroke or traumatic brain injury, but are also profoundly altered in chronic neurodegenerative conditions such as Alzheimer's disease. While disease-altered astrocytes are often referred to as reactive, this does not represent a single cellular state or group of states, but a shift in astrocyte properties that is determined by the type of insult as well as spatio-temporal factors. Such changes can accelerate disease progression due to astrocytes neglecting their normal homeostatic neuro-supportive roles, as well as by gaining active neuro-toxic properties. However, other aspects of astrocytic responses to chronic disease can include the induction of adaptive-protective pathways. This is particularly the case when considering antioxidant defences, which can be up-regulated in many cell types, including astrocytes, in response to stresses, sometimes in concert with the activation of detoxification and proteostasis pathways. Protective responses, whilst potentially serving to mitigate neuronal dysfunction, may ultimately fail due to being insufficiently strong, or be offset by other deleterious changes to astrocytes occurring in parallel. Nevertheless, a greater understanding of early adaptive-protective responses of astrocytes to neurodegenerative disease pathology may point to ways in which these responses may be harnessed for therapeutic effect.

Graphical abstract

Highlights

• •

  Astrocytes play important homeostatic roles in the healthy brain.

• •

  They are widely known to change for the worse in neurodegenerative disease.

• •

  Changes include abandoning their homeostatic roles and becoming actively neurotoxic.

• •

  Some responses however are protective and may be relevant to early stage disease.