From Proteinopathy to Immunopathy in Alzheimer's Disease—A Role for Astrocytic Calcineurin?

The contemporary version of the most widely accepted model of Alzheimer's disease (AD), the β-amyloid cascade hypothesis, identifies β-amyloid oligomers as the primary neurotoxic species.Arising either from genetic mutations or environmental and lifestyle predisposing factors (collectively termed the exposome), β-amyloid oligomers gradually disrupt homeostatic cellular processes.At the cellular level, these alterations largely converge on two central pathobiological domains: proteinopathy (the disruption of cellular protein homeostasis) and immunopathy (the activation of immune-inflammatory pathways).Alterations of protein homeostasis and immune-inflammatory reactions evolve concomitantly in a self-amplifying vicious cycle that shapes the spatio-temporal progression of AD.A mechanistic understanding of this proteinopathy-immunopathy crosstalk is fundamental to identifying preventive and disease-modifying therapies.Here, we propose that the calcium/calmodulinactivated phosphatase calcineurin, expressed in astroglial cells, serves as a pivotal molecular switch between protein homeostasis and neuroinflammation, representing a potential target for therapeutic intervention.