THE ROLE OF ASTROCYTIC α7 NICOTINIC ACETYLCHOLINE RECEPTORS IN NEUROINFLAMMATION-MEDIATED COGNITIVE IMPAIRMENT

Abstract

An important component of Alzheimer's disease (AD) is neuroinflammation. In the periphery, α7 nAChR activation inhibits macrophage production of pro-inflammatory cytokines. In the CNS, α7 nAChRs are enriched in brain regions affected early in AD. However, α7 nAChR expression is not restricted to neurons; these receptors are highly enriched within the CNS immune system. We have previously reported important roles for astrocytic α7 nicotinic acetylcholine receptor (nAChR)-Aβ interaction with subsequent effects on cognition. To refine these studies, we sought to test the hypothesis that astrocytic α7 nAChRs serve an analogous anti-inflammatory role to that in the periphery. To test our hypothesis, we generated mice in which the fourth exon of the α7 nAChR gene (Chrna7) is flanked by loxP sites (α7nAChRflox). We then crossed α7nAChRflox mice with mice expressing Cre recombinase driven by the glial acidic fibrillary protein (GFAP) and studied neuroinflammatory responses and cognition following intracerebroventricular (ICV) injection of LPS (10 ng); a dose that induces transient neuroinflammatory responses without measurable peripheral inflammation. We studied hemizygous astrocytic α7nAChR (GFAP-A7+/-) knockdown mice compared to α7nAChRflox+/- littermates. Whereas sham and LPS ICV-injected α7nAChRflox+/- littermates performed similarly in hippocampus-dependent associative learning and memory, GFAP-A7+/- mice were impaired. Bio-Plex analysis of serum, hippocampus and cholinergic basal forebrain revealed that α7nAChRflox+/- littermates mounted both a pro- and anti-inflammatory response to ICV LPS; GFAP-A7+/- mice did not. However, GFAP-A7+/- mice exhibited pronounced microglia activation and tau hyperphosphorylation in hippocampal structures. Morphometric analysis showed that GFAP-A7+/- mice presented with blunted astrocyte response to LPS challenge. Currently, we are using cultured astrocytes from hemizygous GFAP-Cre α7nAChR knockdown mice and α7nAChRflox littermates to decipher mechanistic details. Blunted astrocyte response, absence of an anti-inflammatory response, microglia activation and tau pathology resulting from ICV LPS injection suggests that knockdown of α7 nAChRs in astrocytes triggers a feed-forward pro-inflammatory response to elicit AD-like cognitive deficits. Thus, similar to their role in the periphery, astrocytic α7 nAChRs serve an anti-inflammatory role in the CNS. This has significant implications for AD since Aβ binds α7 nAChRs to silence these receptors.