Alzheimer's disease (AD) is characterized by severe neuronal loss; however, the mechanisms by which neurons die remain elusive. Necroptosis, a programmed form of necrosis, is executed by the mixed lineage kinase domain-like (MLKL) protein, which is triggered by receptor-interactive protein kinases (RIPK) 1 and 3. We found that necroptosis was activated in postmortem human AD brains, positively correlated with Braak stage, and inversely correlated with brain weight and cognitive scores. In addition, we found that the set of genes regulated by RIPK1 overlapped significantly with multiple independent AD transcriptomic signatures, indicating that RIPK1 activity could explain a substantial portion of transcriptomic changes in AD. Furthermore, we observed that lowering necroptosis activation reduced cell loss in a mouse model of AD. We anticipate that our findings will spur a new area of research in the AD field focused on developing new therapeutic strategies aimed at blocking its activation.

The search for a method that utilizes biological information to predict humans’ place of origin has occupied scientists for millennia. Over the past four decades, scientists have employed genetic data in an effort to achieve this goal but with limited success. While biogeographical algorithms using next-generation sequencing data have achieved an accuracy of 700 km in Europe, they were inaccurate elsewhere. Here we describe the Geographic Population Structure (GPS) algorithm and demonstrate its accuracy with three data sets using 40,000–130,000 SNPs. GPS placed 83% of worldwide individuals in their country of origin. Applied to over 200 Sardinians villagers, GPS placed a quarter of them in their villages and most of the rest within 50 km of their villages. GPS’s accuracy and power to infer the biogeography of worldwide individuals down to their country or, in some cases, village, of origin, underscores the promise of admixture-based methods for biogeography and has ramifications for genetic ancestry testing.

Precociously disseminated cancer cells may seed quiescent sites of future metastasis if they can protect themselves from immune surveillance. However, there is little knowledge about how such sites might be achieved. Here, we present evidence that prostate cancer stem-like cells (CSC) can be found in histopathologically negative prostate draining lymph nodes (PDLN) in mice harboring oncogene-driven prostate intraepithelial neoplasia (mPIN). PDLN-derived CSCs were phenotypically and functionally identical to CSC obtained from mPIN lesions, but distinct from CSCs obtained from frank prostate tumors. CSC derived from either PDLN or mPIN used the extracellular matrix protein Tenascin-C (TNC) to inhibit T-cell receptor-dependent T-cell activation, proliferation, and cytokine production. Mechanistically, TNC interacted with a5b1 integrin on the cell surface of T cells, inhibiting reorganization of the actin-based cytoskeleton therein required for proper T-cell activation. CSC from both PDLN and mPIN lesions also expressed CXCR4 and migrated in response to its ligand CXCL12, which was overexpressed in PDLN upon mPIN development. CXCR4 was critical for the development of PDLN-derived CSC, as in vivo administration of CXCR4 inhibitors prevented establishment in PDLN of an immunosuppressive microenvironment. Taken together, our work establishes a pivotal role for TNC in tuning the local immune response to establish equilibrium between disseminated nodal CSC and the immune system. Cancer Res; 75(10); 2095-108. Ó2015 AACR.

Circulating 45 and 62 kDa antibodies targeting the cerebellum were previously associated with Autism Spectrum Disorder (ASD), lower adaptive/cognitive function and aberrant behaviors. Moreover, 37, 39 and 73 kDa maternal antibodies (mAb) targeting the fetal brain were previously correlated with broad autism spectrum, irritability, abnormal brain enlargement and impaired expressive language. The present study aims towards clinically characterizing individuals with brain-targeted IgG and/or exposed to maternal antibrain antibodies in a large sample of Italian autistic children (N = 355), their unaffected siblings (N = 142) and mothers (N = 333). The presence of patient- and mother-produced anti-brain antibodies does not confer increased risk of autism within the same sibship. However, the 45 and 62 kDa antibodies are correlated with autism severity: the 45 kDa Ab is associated with cognitive impairment and lower scores at the Vineland Adaptive Behavior Scales, the 62 kDa Ab with motor stereotypies, while both correlate with larger head circumference (all P < 0.05). On the other hand, maternal 37, 39 and 73 kDa antibrain antibodies, either alone or in combination, are correlated with impaired verbal and non-verbal language development, neurodevelopmental delay and sleep/wake cycle disturbances in their autistic children (P < 0.05). Presence of the 62 kDa autoAb in the child is significantly associated with presence of the 39 and/or 73 kDa antibodies in his/her mother. Our results confirm and extend previous observations in an ethnically distinct sample, providing further evidence of a pathomorphic role for antibrain antibodies in autism while demonstrating their familial clustering.

Key Points• FOXP3 functions as a negative regulator of T-cell proliferation and cytokine production in human conventional T cells.• Expression of FOXP3 in human Th17 cells functions to suppress IFN-␥ production. IntroductionExpression of the transcription factor forkhead box P3 (FOXP3) in T-regulatory cells (Tregs) is necessary and sufficient for Tregs to suppress the effector function of conventional T (Tconv) cells. In cooperation with other transcription factors, including NFAT and Runx1, and the Th17-associated transcription factors ROR-␥t and ROR␣, FOXP3 establishes the Treg program by repressing or trans-activating defined genes. 1,2 The molecular mechanisms of FOXP3-mediated regulation of gene transcription are not clearly defined, but repression involves interactions with the histone acetyl-transferase TIP60, the histone deacetylase HDAC7, and linker histone H1.5. 3,4 After its discovery in Tregs, it was soon demonstrated that FOXP3 is also expressed transiently in human Tconv cells after TCR activation. [5][6][7][8][9][10][11] Similarly, another Treg-associated transcription factor, Helios, can also be expressed on activation. 12 The major differences between FOXP3 in Tregs and Tconv cells are in stability and expression levels. In Tregs, the Treg-specific demethylated region (TSDR) region of the FOXP3 promoter is demethylated, permitting high and stable expression. 13 Conversely, in Tconv cells, the TSDR is methylated, resulting in transient expression of FOXP3 that never reaches the intensity of that in similarly activated Tregs. 6,7,9,13 Transient FOXP3 expression in Tconv cells does not prevent cytokine production and/or confer suppressive capacity, although this has been a point of controversy. [5][6][7][8][9][10][11] Another role for FOXP3 is to antagonize Th17 cell development. Interaction of FOXP3 with ROR-␥t or Runx1 inhibits IL-17 production, 1 whereas ROR-␥t together with hypoxia-inducible factor 1␣ inhibits FOXP3. 14 Therefore, in a tolerogenic environment that includes TGF␤, FOXP3 suppresses Th17 cell development and Treg differentiation prevails. In contrast, in inflammatory environments hypoxia inducible factor1␣ promotes ROR-␥t expression, causing degradation of FOXP3, promotion of Th17 cell development, and blockade of Treg differentiation. 14 Beyond this "tug-of-war" during differentiation, Tregs and Th17 cells may have the ability to interconvert. FOXP3 ϩ IL-17-secreting cells exist in vivo, 15-17 but it is not clear whether these cells are Tregs that have begun to secrete IL-17 or if they are Th17 cells that have begun to express FOXP3.Despite clear evidence that FOXP3 is expressed in Tconv cells, its function remained unknown. In the present study, we investigated the role of FOXP3 in human Tconv cells and found that FOXP3-deficient Tconv cells proliferated to a greater extent and produced greater amounts of cytokines than wild-type (WT) Tconv cells. Furthermore, FOXP3 was highly expressed in activated Th17 The online version of this article contains a data supplement.The publicati...

The lack of effective treatments for Alzheimer’s disease (AD) is alarming considering the number of people currently affected by this disorder and the projected increase over the next few decades. Elevated homocysteine levels double the risk of developing AD. Choline, a primary dietary source of methyl groups, converts homocysteine to methionine and reduces age-dependent cognitive decline. Here, we tested the transgenerational benefits of maternal choline supplementation (ChS; 5.0 g/kg choline chloride) in two generations (Gen) of APP/PS1 mice. We first exposed 2.5-month-old mice to the ChS diet and allowed them to breed with each other to generate Gen-1 mice. Gen-1 mice were exposed to the ChS diet only during gestation and lactation; once weaned at postnatal day 21, Gen-1 mice were then kept on the control diet for the remainder of their life. We also bred a subset of Gen-1 mice to each other and obtained Gen-2 mice; these mice were never exposed to ChS. We found that ChS reduced Aβ load and microglia activation, and improved cognitive deficits in old Gen-1 and Gen-2 APP/PS1 mice. Mechanistically, these changes were linked to a reduction in brain homocysteine levels in both generations. Further, RNA-Seq data from APP/PS1 hippocampal tissue revealed that ChS significantly changed the expression of 27 genes. These genes were enriched for inflammation, histone modifications, and neuronal death functional classes. Our results are the first to demonstrate a transgenerational benefit of ChS and suggest that modifying the maternal diet with additional choline reduces AD pathology across multiple generations.

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The current study employed next-generation RNA sequencing to examine gene expression differences related to brain aging, cognitive decline, and hippocampal subfields. Young and aged rats were trained on a spatial episodic memory task. Hippocampal regions CA1, CA3, and the dentate gyrus were isolated. Poly-A mRNA was examined using two different sequencing platforms, Illumina, and Ion Proton. The Illumina platform was used to generate seed lists of genes that were statistically differentially expressed across regions, ages, or in association with cognitive function. The gene lists were then retested using the data from the Ion Proton platform. The results indicate hippocampal subfield differences in gene expression and point to regional differences in vulnerability to aging. Aging was associated with increased expression of immune response-related genes, particularly in the dentate gyrus. For the memory task, impaired performance of aged animals was linked to the regulation of Ca2+ and synaptic function in region CA1. Finally, we provide a transcriptomic characterization of the three subfields regardless of age or cognitive status, highlighting and confirming a correspondence between cytoarchitectural boundaries and molecular profiling.