NFATs and Alzheimer's Disease

Abstract

Nuclear factor of activated T cells (NFAT) is a transcription factor that translocates from cytosol to nucleus following dephosphorylation by the Ca(2+)/calmodulin dependent protein phosphatase calcineurin (CN). In nervous tissue, aberrant CN signaling is increasingly linked to a variety of pathologic features associated with Alzheimer's disease (AD), including synaptic dysfunction, glial activation, and neuronal death. Consistent with this linkage, our recent work on postmortem human hippocampal tissue discovered increased nuclear accumulation of select NFAT isoforms at different stages of AD. Some of these changes occurred at the early stages of the disease process and/or paralleled diminishing cognitive status. In addition, inhibition of astrocytic NFAT activity in primary cultures of neurons and glia dampened glutamate levels and alleviated neuronal death in response to pathogenic amyloid-β peptides. In this article, we discuss our recent findings and expand upon the possible isoform specific contributions of NFATs to the progression of AD. We also consider the possible benefits of using NFAT inhibitors to treat AD and other neurodegenerative disorders, as well.

Figure 1. Working model for the role of CN/NFAT signaling in AD

During aging, gradual dysregulation of Ca²⁺, oxidative stress, and/or neuroinflammation lead to increased production of Aβ, increased activation of CN or both. In turn, aberrant CN activity leads to synaptic dysfunction and neuroinflammation, in part through increased stimulation of NFAT1. This chain of events leads to mild cognitive impairment (MCI). Note that cyclical interactions between neuroinflammatory processes (i.e. glial activation) and synaptic dysfunction) can maintain the CN/NFAT1 pathway in an activated state, which helps perpetuate deleterious neuronal and glial activities. NFAT1 also helps exacerbate amyloid toxicity through upregulation of BACE1 (see text). Eventually, these interactions progress to a degenerative state (i.e. Alzheimer’s disease) characterized by severe amyloidosis and severe Ca²⁺ dyshomeostasis leading to greater CN activity. CN triggers neuritic atrophy and cell death cascades through preferential activation of NFAT3.

Figure 2. The NFAT inhibitor, VIVIT, reduces astrocyte activation in AD mice

A and B, photomicrographs of a GFAP-labeled coronal section from a 14-month-old APP/PS1 mouse treated intraventricularly for two weeks with 11R-VIVIT. Dashed boxes indicate regions of higher magnification shown in A1 and A2 (ipsilateral, VIVIT-treated hemisphere—Ipsi) and B1 and B2 (contralateral hemisphere—contra). C, GFAP-labeled coronal section (Ipsilateral hemisphere) from a 14-month-old APP/PS1 mouse treated for two weeks with 11R-IVEET control peptide. Dashed boxes indicate regions of higher magnification shown in C1 and C2. IVEET-treated mice and the contralateral hemisphere of VIVIT-treated mice appear to express more numerous and more ramified astrocytes relative to the ipsilateral hemisphere of VIVIT-treated mice. CA1 = cornu ammonis 1 pyramidal cell layer.