Neurofibrillary tangles (NFTs), composed of intracellular filamentous aggregates of hyperphosphorylated protein tau, are one of the pathological hallmarks of Alzheimer's disease (AD). Tau phosphorylation is regulated by the equilibrium between activities of its protein kinases and phosphatases; unbalance of these activities is proposed to be a reasonable causative factor to the disease process. Glycogen synthase kinase 3beta (GSK3beta) is one of the most important protein kinase in regulating tau phosphorylation; overexpression of active GSK3beta causes ADlike hyperphosphorylation of tau. Protein phosphatase 2A (PP2A) is the major phosphatase that dephosphorylates tau; it was demonstrated that highly conserved carboxyl-terminal sequence of PP2A C-subunit is a focal point for phosphatase regulation. This is the site of a reversible methyl esterification reaction that controls AB_{alpha}C heterotrimers formation. Here we demonstrate that GSK3beta and PP2A genes were upregulated by inhibiting methylation reactions through B vitamin deficiency. In this condition, methylated catalytic subunit PP2Ac was decreased, leading to reduced PP2A activity. By contrast, we observed GSK3beta protein increase and a modulation in phosphorylation sites that regulate GSK3beta activity. Therefore, one-carbon metabolism alteration seems to be a cause of deregulation of the equilibrium between GSK3beta and PP2A, leading to abnormal hyperphosphorylated tau.

In the present study we investigated the role of donor specific HLA antibodies (DSA) and donor KIR repertoire characteristics in a group of 18 patients affected by haemoglobinopathies who underwent haploidentical T cell depleted transplantation. Among these patients, 8 rejected the transplant while 10 had complete donor chimerism (CC). Five out of 8 patients (62.5%) who rejected graft had anti-HLA antibodies in the sera collected before transplant, while only 1 patient out of 10 (10%) with CC showed their presence (p=0,042). Notably, of the 5 HLA antibodies positive patients who rejected the graft 3 had DSA (2 for class I and 1 for class I and II) while none of the patients with CC had DSA. Among the 8 patients that experienced graft failure 4 were transplanted with a donor characterized by the lack of NK alloreactivity and 5 with a donor with a B content value <2. Although we analyzed a small cohort of patients, our data indicated that the presence of anti-HLA antibodies in patient sera, but not donor KIR characteristics, correlates with graft failure thus suggesting that analysis of anti-HLA antibodies should be taken into account in haploidentical transplant setting.

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