Abstract
In humans, dysfunctional primary cilia result in Bardet-Biedl syndrome (BBS), which presents with clinical features including intellectual disabilities, obesity, and retinal degeneration, and, in mouse models, the added feature of hydrocephalus. We observed increased Glial Fibrillary Acidic Protein (GFAP) immunoreactivity in BBS mouse brains. Increased GFAP expression is a hallmark of astrocyte reactivity that is associated with microglia activation and neuro-inflammation. To gain a better understanding of reactive astrocytes observed in BBS mice, we used two mouse models of BBS8, a BBSome protein, to characterize the reactive astrocyte phenotype. The finding of reactive astrocytes in young BBS mouse brains led us to hypothesize that loss of BBSome function leads to reactive astrocytes prior to hydrocephalus and obesity. By using two mouse models of BBS8, a congenital BBS8 knockout with hydrocephalus, and a tamoxifen-inducible BBS8 knockout without hydrocephalus, we were able to molecularly phenotype the reactive astrocytes. Molecular phenotype of reactive astrocytes shows differential regulation of inducers of Pan, A1 neurotoxic, and A2 neuroprotective astrocytes that are significantly altered in brains of both congenital and induced knockouts of BBS8, but without microglia activation. We find evidence for neuroinflammation in the brains of congenital knockout mice, but not in induced knockout mice. Protein levels of GFAP, SERPINA3N and post-synaptic density 95 (PSD95) are significantly increased in congenital knockout mice, but remain unchanged in induced knockout mice. Thus, despite the reactive astrocyte phenotype being present in both models, the molecular signature of reactive astrocytes in BBS8 mice models are distinct. Together, these findings suggest that BBS8, and by extension the BBSome, plays a role in neuro-astrocyte functions independent of hydrocephalus, and its dysregulation is associated with astrocyte reactivity without microglia activation. (Total word count 278).
Highlights
Neuro-inflammation of the central nervous system (CNS) is marked by the presence of reactive astrocytes [1]
Since reactive astrocytes are associated with reactive microglia, neuroinflammation, and altered synaptic function, we examined whether reactive astrocytes observed in BBS8 mice were associated with their molecular phenotypes of reactive astrocytes
In this study we used western blot analyses to quantify the protein expressions of various molecular markers associated with reactive astrocytes and microglia from whole brain lysates to gain a better understanding of molecular phenotypes of reactive astrocytes in BBS8 mice
Summary
Neuro-inflammation of the central nervous system (CNS) is marked by the presence of reactive astrocytes [1]. Reactive astrocytes, which originate in response to an insult to the brain, are highly disease and context specific [7, 8]. This makes it difficult to assign a specific, unified molecular signature to reactive astrocytes. Recent work has identified two different subtypes of reactive astrocytes: A1 and A2 [9]. Subtype A1 reactive astrocytes are neurotoxic and are induced by reactive microglia, which are the primary immune cell in the brain. A1 reactive astrocytes weaken synapses, disrupt synaptic signaling, and cause the death of neurons and myelin-producing oligodendrocytes. Subtype A2 reactive astrocytes, on the other hand, tend to be neuroprotective.
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