Alzheimer’s disease (AD) is the most common cause of dementia. The pathophysiology of this disease is characterized by the accumulation of amyloid-β, leading to the formation of senile plaques, and by the intracellular presence of neurofibrillary tangles based on hyperphosphorylated tau protein. In the therapeutic approach to AD, we can identify three important fronts: the approved drugs currently available for the treatment of the disease, which include aducanumab, donepezil, galantamine, rivastigmine, memantine, and a combination of memantine and donepezil; therapies under investigation that work mainly on Aβ pathology and tau pathology, and which include γ-secretase inhibitors, β-secretase inhibitors, α-secretase modulators, aggregation inhibitors, metal interfering drugs, drugs that enhance Aβ clearance, inhibitors of tau protein hyperphosphorylation, tau protein aggregation inhibitors, and drugs that promote the clearance of tau, and finally, other alternative therapies designed to improve lifestyle, thus contributing to the prevention of the disease. Therefore, the aim of this review was to analyze and describe current treatments and possible future alternatives in the therapeutic approach to AD.

The nuclear import of the nuclear factor of activated T cells (NFAT)-family transcription factors is initiated by the protein phosphatase calcineurin. Here we identify a regulatory region of NFAT1, N terminal to the DNA-binding domain, that controls nuclear import of NFAT1. The regulatory region of NFAT1 binds directly to calcineurin, is a substrate for calcineurin in vitro, and shows regulated subcellular localization identical to that of full-length NFAT1. The corresponding region of NFATc likewise binds calcineurin, suggesting that the efficient activation of NFAT1 and NFATc by calcineurin reflects a specific targeting of the phosphatase to these proteins. The presence in other NFAT-family transcription factors of several sequence motifs from the regulatory region of NFAT1, including its probable nuclear localization sequence, indicates that a conserved protein domain may control nuclear import of all NFAT proteins.

Transcription factors of the nuclear factor of activated T cells (NFAT) family are thought to regulate the expression of a variety of inducible genes such as interleukin-2 (IL-2), IL-4, and tumor necrosis factor-α. However, it remains unresolved whether NFAT proteins play a role in regulating transcription of the interferon- γ (IFN-γ) gene. Here it is shown that the transcription factor NFAT1 (NFATc2) is a major regulator of IFN-γ production in vivo. Compared with T cells expressing NFAT1, T cells lacking NFAT1 display a substantial IL-4–independent defect in expression of IFN-γ mRNA and protein. Reduced IFN-γ production by NFAT1−/−× IL-4−/− T cells is observed after primary in vitro stimulation of naive CD4+ T cells, is conserved through at least 2 rounds of T-helper cell differentiation, and occurs by a cell-intrinsic mechanism that does not depend on overexpression of the Th2-specific factors GATA-3 and c-Maf. Concomitantly, NFAT1−/−× IL-4−/− mice show increased susceptibility to infection with the intracellular parasiteLeishmania major. Moreover, IFN-γ production in a murine T-cell clone is sensitive to the selective peptide inhibitor of NFAT, VIVIT. These results suggest that IFN-γ production by T cells is regulated by NFAT1, most likely at the level of gene transcription.