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Nicastrin is a protein recently discovered associated to presenilins and involved in the production of amyloid beta peptide that accumulates in Alzheimer''s disease (AD) brain. In this study the nicastrin gene was examined for unknown mutations and polymorphisms in 104 patients with familial AD (52 early-onset and 52 late-onset), 174 sporadic AD and 191 healthy neurological controls of Italian origin. The scanning of the nicastrin gene identified a missense mutation (N417Y) in two patients with sporadic AD, in an early-onset familial AD and in a young control subject. Furthermore, we found two silent mutations and four intronic polymorphisms, three of them co-segregating in a single haplotype. We found some differences in the distribution of genotype alterations in the AD population compared to the controls. However, our data together with other evidence did not support the pathological role of missense mutation N417Y. [Copyright &y& Elsevier]

• In erythrocytes of AD patients the anion transporter band3 is highly phosphorylated. • Activation of lyn kinase and downregulation of tyrosine phosphatase occur. • Band3 phosphorylation correlates negatively with the cognitive status of patients. • Treatment of erythrocytes with Aβ1–42 peptide induces both band3 phosphorylation and lyn activation. Alzheimer's disease (AD) is the most prevalent type of dementia affecting older people. The identification of biomarkers is increasingly important and would be crucial for future therapy. Here, we demonstrated that in AD erythrocytes: (i) the anion transporter band3 is highly phosphorylated; (ii) the lyn kinase is phosphorylated and activated; (iii) the tyrosine phosphatase activity is downregulated, with a significant inverse correlation between band3 phosphorylation and disease progression, as revealed by Mini Mental State Examination score. Finally, we showed that in normal erythrocytes, treated in vitro with Aβ1–42 peptide, both band3 phosphorylation and lyn activation occurs. These results suggest that modulation of tyrosine phosphorylation signaling may be evaluated as a potential peripheral marker in AD. [ABSTRACT FROM AUTHOR]

Highlights: [•] Familial Alzheimer's disease (FAD) is attracting a growing scientific interest. [•] PSEN2 mutations represent the less common cause of FAD. [•] Mutations of the PSEN2 gene are mostly associated to a “typical” AD phenotype. [•] Improved phenotyping of FAD cases may have a relevant impact. [Copyright &y& Elsevier]

Abstract: Progranulin (PGRN) is a widely expressed multifunctional protein, involved in regulation of cell growth and cell cycle progression with a possible involvement in neurodegeneration. We looked for PGRN regulation in three different human neuroblastoma cell lines, following exposure to two different stimuli commonly associated to neurodegeneration: hypoxia and oxidative stress. For gene and protein expression analysis we carried out a quantitative RT-PCR and western blotting analysis. We show that PGRN is strongly up-regulated by hypoxia, through the mitogen-actived protein kinase (MAPK)/extracellular signal-regulated kinase (MEK) signaling cascade. PGRN is not up-regulated by H2O2-induced oxidative stress. These results suggest that PGRN in the brain could exert a protective role against hypoxic stress, one of principal risk factors involved in frontotemporal dementia pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Presenilin-1 (PSEN-1) is a component of the γ-secretase complex involved in β-amyloid precursor protein (βAPP) processing. To date about 140 pathogenic mutations in the PSEN-1 gene have been identified and their main biochemical effect is to increase the production of the fibrillogenic peptide Aβ(1–42). An exception is the PSEN-1 [E318G] mutation that does not alter Aβ(1–42) generation and is generally considered a non-pathogenic polymorphism. Nevertheless, this mutation was reported to be a genetic risk factor for familial Alzheimer''s disease (FAD) in the Australian population. To independently confirm this indication, we performed a case-control association study in the Italian population. We found a significant association (p <0.05, Fisher''s exact test) between the presence of PSEN-1 [E318G] and FAD. In addition, on measuring the Aβ(1–42) and Aβ(1–40) concentrations in fibroblast-conditioned media cultured from PSEN-1 [E318G] carriers and PSEN-1 [wild type] controls we noted a significant decrease (p <0.05, Mann–Whitney test) in the Aβ(1–42)/Aβ(1–40) ratio in PSEN-1 [E318G] carriers, suggesting a peculiar biochemical effect of this mutation. [Copyright &y& Elsevier]

Abstract: We describe the genetic analysis of an Alzheimer''s disease (AD) sample derived from a genetically isolated population. Genetic assessment included the analysis of genes involved in AD, such as the genes for amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). We also assessed genes for some proteins that constitute the γ-secretase complex: nicastrin (NCSTN), presenilin enhancer-2 (PEN2), in addition to the AD risk factor apolipoprotein E (APOE). Using polymerase chain reaction and single strand conformational polymorphism method, screens for APP, PSEN1 and PSEN2 genes revealed one mutation in PSEN1. Furthermore, we found an intronic +17G>C polymorphism in PEN2 which, in homozygous form, was greater in early onset Alzheimer''s disease (EOAD) compared to controls, and one haplotype in the NCSTN gene which was linked to EOAD and familial AD (FAD). Finally, the genotyping of APOE confirmed that the ɛ4 allele could be a risk factor for the onset of AD, in particular for FAD subjects. In conclusion, these results show the existence of Sardinian genetic peculiarities, essential in studies regarding genetically inherited and multifactorial disorders, as AD. [Copyright &y& Elsevier]

The purpose of this study was to develop an easy and minimally invasive assay to detect a plasma miRNA profile in frontotemporal dementia (FTD) patients, with the final aim of discriminating between FTD patients and healthy controls (HCs). After a global miRNA profiling, significant downregulation of miR-663a, miR-502-3p, and miR-206 (p = 0.0001, p = 0.0002, and p = 0.02 respectively) in FTD patients was confirmed when compared with HCs in a larger case-control sample. Moreover, miR-663a and miR-502-3p showed significant differences in both genders, whereas miR-206, only in male subjects. To obtain a discriminating measure between FTD patients and HCs, we calculated a combined score of the 3 miRNAs by applying a Bayesian approach and obtaining a classifier with an accuracy of 84.4%. Moreover, for men, combined miRNA levels showed an excellent sensitivity (100%) and a good specificity (87.5%) in distinguishing FTD patients from HCs. All these findings open new hypotheses in the pathophysiology and new perspectives in the diagnosis of a complex pathology as FTD. • Discovery analysis of 752 miRNAs identified a dysregulation of 10 miRNAs in FTD patients. • Validation study confirmed a downregulation of miR-663a, miR-502-3p, and miR-206 in FTD patients. • A combined score was calculated with 84.4% accuracy to discriminate FTD patients from HCs. • Analyzing by gender, differences of miR-206 levels were specific for men. • Predicted target genes of the 3 miRNAs are involved in several neurological pathways. [ABSTRACT FROM AUTHOR]

Abstract: We conducted a genome-wide association study in a cohort of 176 Italian Alzheimer''s disease (AD) patients with extreme phenotype of response to cholinesterase inhibitors. Patients were classified into responders in case of positive, stable, or ≤1 worsening of mini-mental state examination score and into nonresponders if >3 points worsening during a median follow-up of 0.85 years of treatment. Forty-eight single-nucleotide polymorphisms were selected for replication in 198 additional AD-treated patients. By using the dichotomous response trait and a quantitative trait approach (change of mini-mental state examination), a nominal replication and evidence of association when combining data were achieved for 2 single-nucleotide polymorphisms associated with response to treatment: rs6720975A (p combined = 2.9 × 10−5, beta regression coefficient: 1.61) and rs17798800A (p combined = 6.8 × 10−6, odds ratio = 0.38, 95% confidence interval = 0.25–0.58). Rs6720975 maps in the intronic region of PRKCE, a protein kinase involved in several cellular functions, whereas rs17798800 is intergenic and, according to expression quantitative trait locus (eQTL) analysis, it acts as a cis-regulator of NBEA, an A kinase–anchoring protein playing a substantial role in the maturation of the nervous system. Despite its limitations, this project paves the way for the application of personalized medicine in AD patients and for collaborative efforts in this field. [Copyright &y& Elsevier]