PP165—Evaluation of JNJ-26489112, a Novel Antiepileptic Drug: A Placebo-Controlled, Exploratory Study

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Tau-Mediated Nuclear Depletion and Cytoplasmic Accumulation of SFPQ in Alzheimer's and Pick's Disease

Tau dysfunction characterizes neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). Here, we performed an unbiased SAGE (serial analysis of gene expression) of differentially expressed mRNAs in the amygdala of transgenic pR5 mice that express human tau carrying the P301L mutation previously identified in familial cases of FTLD. SAGE identified 29 deregulated transcripts including Sfpq that encodes a nuclear factor implicated in the splicing and regulation of gene expression. To assess the relevance for human disease we analyzed brains from AD, Pick's disease (PiD, a form of FTLD), and control cases. Strikingly, in AD and PiD, both dementias with a tau pathology, affected brain areas showed a virtually complete nuclear depletion of SFPQ in both neurons and astrocytes, along with cytoplasmic accumulation. Accordingly, neurons harboring either AD tangles or Pick bodies were also depleted of SFPQ. Immunoblot analysis of human entorhinal cortex samples revealed reduced SFPQ levels with advanced Braak stages suggesting that the SFPQ pathology may progress together with the tau pathology in AD. To determine a causal role for tau, we stably expressed both wild-type and P301L human tau in human SH-SY5Y neuroblastoma cells, an established cell culture model of tau pathology. The cells were differentiated by two independent methods, mitomycin C-mediated cell cycle arrest or neuronal differentiation with retinoic acid. Confocal microscopy revealed that SFPQ was confined to nuclei in non-transfected wild-type cells, whereas in wild-type and P301L tau over-expressing cells, irrespective of the differentiation method, it formed aggregates in the cytoplasm, suggesting that pathogenic tau drives SFPQ pathology in post-mitotic cells. Our findings add SFPQ to a growing list of transcription factors with an altered nucleo-cytoplasmic distribution under neurodegenerative conditions

Selective Impairment of Long-Range Default Mode Network Functional Connectivity as a Biomarker for Preclinical Alzheimer's Disease in People with Down Syndrome.

BackgroundDown syndrome (DS) is associated with increased risk for Alzheimer's disease (AD). In neurotypical individuals, clinical AD is preceded by reduced resting state functional connectivity in the default mode network (DMN), but it is unknown whether changes in DMN connectivity predict clinical onset of AD in DS.ObjectiveDoes lower DMN functional connectivity predict clinical onset of AD and cognitive decline in people with DS?MethodsResting state functional MRI (rsfMRI), longitudinal neuropsychological, and clinical assessment data were collected on 15 nondemented people with DS (mean age = 51.66 years, SD = 5.34 years, range = 42-59 years) over four years, during which 4 transitioned to dementia. Amyloid-β (Aβ) PET data were acquired on 13 of the 15 participants. Resting state fMRI, neuropsychological, and clinical assessment data were also acquired on an independent, slightly younger unimpaired sample of 14 nondemented people with DS (mean age = 44.63 years, SD = 7.99 years, range = 38-61 years).ResultsLower functional connectivity between long-range but not short-range DMN regions predicts AD diagnosis and cognitive decline in people with DS. Aβ accumulation in the inferior parietal cortex is associated with lower regional DMN functional connectivity.ConclusionReduction of long-range DMN connectivity is a potential biomarker for AD in people with DS that precedes and predicts clinical conversion

Molecular mechanism of membrane constriction and tubulation mediated by the F-BAR protein Pacsin/Syndapin

Peripheral membrane proteins of the Bin/amphiphysin/Rvs (BAR) and Fer-CIP4 homology-BAR (F-BAR) family participate in cellular membrane trafficking and have been shown to generate membrane tubules. The degree of membrane bending appears to be encoded in the structure and immanent curvature of the particular protein domains, with BAR and F-BAR domains inducing high- and low-curvature tubules, respectively. In addition, oligomerization and the formation of ordered arrays influences tubule stabilization. Here, the F-BAR domain-containing protein Pacsin was found to possess a unique activity, creating small tubules and tubule constrictions, in addition to the wide tubules characteristic for this subfamily. Based on crystal structures of the F-BAR domain of Pacsin and mutagenesis studies, vesiculation could be linked to the presence of unique structural features distinguishing it from other F-BAR proteins. Tubulation was suppressed in the context of the full-length protein, suggesting that Pacsin is autoinhibited in solution. The regulated deformation of membranes and promotion of tubule constrictions by Pacsin suggests a more versatile function of these proteins in vesiculation and endocytosis beyond their role as scaffold proteins

Association of a traditional Mediterranean diet and non-Mediterranean dietary scores with all-cause and cause-specific mortality: prospective findings from the Moli-sani Study

Purpose: To evaluate in an Italian general population, the association with mortality of a traditional Mediterranean diet (MD) and non-Mediterranean dietary (non-MD) patterns, and their combined effect, and to test some biomarkers of cardiovascular (CVD) risk as potential mediators of such associations. Methods: Longitudinal analysis on 22,849 men and women aged 65 35 years, recruited in the Moli-sani Study (2005\u20132010), followed up for 8.2 years (median). The MD was assessed by the Mediterranean diet score (MDS). The Dietary Approaches to Stop Hypertension (DASH), the Palaeolithic diet, and the Nordic diet were chosen as reportedly healthy non-MD patterns. Hazard ratios (HR) with 95% confidence intervals (95% CI) were calculated by multivariable Cox regression. Results: Participants reaching higher MDS or DASH diet score experienced lower risk of both all-cause (HR 0.77; 95% CI 0.66\u20130.90 and 0.81; 0.69\u20130.96, respectively, highest vs lowest quartile) and CVD (0.77; 0.59\u20131.00 and 0.81; 0.69\u20130.96, respectively) death risk; risk reduction associated with the Palaeolithic diet was limited to total and other cause death, whereas the Nordic diet did not alter risk of mortality. Increasing adherence to MD was associated with higher survival in each stratum of non-MD diets. Biomarkers of glucose metabolism accounted for 7% and 21.6% of the association between either MDS or DASH diet, respectively, with total mortality risk. Conclusions: Both the traditional MD and DASH diet may reduce risk of all-cause mortality among Italians, as well as risk of dying from cardiovascular causes. The Palaeolithic diet did not appear to reduce cardiovascular risk, while the Nordic eating pattern was unlikely to be associated with any substantial health advantage