Neuroimmunomodulation by calcineurin in aging and Alzheimer's disease

Alzheimer's disease (AD) is a progressive, age-related neurodegenerative disorder which first manifests as profound memory dysfunction. The majority of cases are idiopathic, although advanced age is the greatest risk factor for AD. Recent evidence suggests that pre-fibrillar soluble amyloid-beta (Aβ) underlies an early, progressive loss of synapses that is a hallmark of AD. One of the downstream effects mediated by soluble Aβ aggregates is the hyperactivation of the phosphatase calcineurin (CaN). This important phosphatase is abundant in the nervous system and intimately involved in the mechanisms of memory as well as the immune response. Such a duality places CaN at the crux of neuroimmunomodulation processes. In the present review, we briefly summarize the role of CaN in physiological aging and discuss how CaN hyperactivity could cause the memory impairment, neuroinflammation, and neuronal death that are pathological mechanisms of AD.