The A1 astrocyte paradigm: New avenues for pharmacological intervention in neurodegeneration

Abstract

We recently demonstrated that NLY01, a novel glucagon‐like peptide‐1 receptor agonist, exerts neuroprotective effects in two mouse models of PD in a glia‐dependent manner. NLY01 prevented microglia from releasing inflammatory mediators known to convert astrocytes into a neurotoxic A1 reactive subtype. Importantly, we provided evidence that this neuroprotection was not mediated by a direct action of NLY01 on neurons or astrocytes (e.g., by activating neurotrophic pathways or modulating astrocyte reactivity per se). In the present article, we provide a generalist review of microglia and astrocytes in neurodegeneration and discuss the emerging paradigm of A1 astrocyte neurotoxicity in more detail. We comment on specific inferences that are naturally suggested by our work in this area and the differential level of support it offers to each. Finally, we discuss implications for the overall goal of creating disease‐modifying therapies for PD, survey emerging methodologies for accelerating translational research on glia in neurodegeneration, and describe expected challenges for developing glia‐directed therapies that do not impede essential physiological functions carried out by glia in the CNS. © 2019 International Parkinson and Movement Disorder Society

Reactive Glia Inflammatory Signaling Pathways and Epilepsy

“…Microglia also secretes cytokines, chemokines, and different types of interferons which affect the functionality of reactive astrocytes and neurons [92,93]. To prevent microglia-dependent activation of astrocytes, several authors have used pegylated exedin4 (NLY01), an agonist of glucagon-like peptide1 (GLP1) receptor, which reduces the levels of IL-1α, TNFα, and C1q [42,43]. In the same way, some reports suggest a beneficial effect of propranolol (an antagonist of β-adrenergic receptors) in preventing microglia activation [44] (Table 1).…”

Transgenic minipig model of Huntington's disease exhibiting gradually progressing neurodegeneration

“…It was shown that A1 astrocytes fail to support neuronal survival; in contrast, they can trigger neuronal degeneration (Liddelow et al, 2017). Their increased number was demonstrated in HD as well as in other neurodegenerative diseases (Hinkle et al, 2019). However, the higher presence of A1 astrocytes specifically was not measured in TgHD minipigs.…”

Astrocytes, HIV and the Glymphatic System: A Disease of Disrupted Waste Management?

“…Rationale for this prediction is supported by studies from other neurodegenerative diseases with chronic inflammation and reactive glial cell populations. Upon stressful stimuli, astrocytes become activated from a quiescent state, become reactive and undergo structural and functional changes (Ferrer, 2017 ; Hinkle et al, 2019 ). In this context, astrocytes can be classified into numerous subtypes based on morphology, activation state and anatomical location.…”

“…As discussed in previous sections of the review, some astrocytes are infected by HIV and can produce and release several viral proteins such as Tat, Nef, and Rev due to integrated virus, thereby inducing an A1 phenotype and production of inflammatory factors that damage surrounding cells (Hinkle et al, 2019 ; Shijo et al, 2019 ). Thus, the A1 astrocyte phenotype likely contributes in part to the development HAND (Ances and Clifford, 2008 ).…”