Poly(ADP-ribose)polymerase-1 modulates microglial responses to amyloid β

<p>Abstract</p> <p>Background</p> <p>Amyloid β (Aβ) accumulates in Alzheimer's disease (AD) brain. Microglial activation also occurs in AD, and this inflammatory response may contribute to disease progression. Microglial activation can be induced by Aβ, but the mechanisms by which this occurs have not been defined. The nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) regulates microglial activation in response to several stimuli through its interactions with the transcription factor, NF-κB. The purpose of this study was to evaluate whether PARP-1 activation is involved in Aβ-induced microglial activation, and whether PARP-1 inhibition can modify microglial responses to Aβ.</p> <p>Methods</p> <p>hAPP_J20mice, which accumulate Aβ with ageing, were crossed with PARP-1^-/-mice to assess the effects of PARP-1 depletion on microglial activation, hippocampal synaptic integrity, and cognitive function. Aβ peptide was also injected into brain of wt and PARP-1^-/-mice to directly determine the effects of PARP-1 on Aβ-induced microglial activation. The effect of PARP-1 on Aβ-induced microglial cytokine production and neurotoxicity was evaluated in primary microglia cultures and in microglia-neuron co-cultures, utilizing PARP-1^-/-cells and a PARP-1 inhibitor. NF-κB activation was evaluated in microglia infected with a lentivirus reporter gene.</p> <p>Results</p> <p>The hAPP_J20mice developed microglial activation, reduced hippocampal CA1 calbindin expression, and impaired novel object recognition by age 6 months. All of these features were attenuated in hAPP_J20/<it>PARP-1^-/-</it>mice. Similarly, Aβ_1-42injected into mouse brain produced a robust microglial response in wild-type mice, and this was blocked in mice lacking PARP-1 expression or activity. Studies using microglial cultures showed that PARP-1 activity was required for Aβ-induced NF-κB activation, morphological transformation, NO release, TNFα release, and neurotoxicity. Conversely, PARP-1 inhibition increased release of the neurotrophic factors TGFβ and VEGF, and did not impair microglial phagocytosis of Aβ peptide.</p> <p>Conclusions</p> <p>These results identify PARP-1 as a requisite and previously unrecognized factor in Aβ-induced microglial activation, and suggest that the effects of PARP-1 are mediated, at least in part, by its interactions with NF-κB. The suppression of Aβ-induced microglial activation and neurotoxicity by PARP-1 inhibition suggests this approach could be useful in AD and other disorders in which microglial neurotoxicity may contribute.</p

Brain energy rescue:an emerging therapeutic concept for neurodegenerative disorders of ageing

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner — a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes

Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin

Recent genomic analyses of pathologically-defined tumor types identify “within-a-tissue” disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head & neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multi-platform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All datasets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies

The Somatic Genomic Landscape of Glioblastoma

We describe the landscape of somatic genomic alterations based on multi-dimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer

Collaborative software for traditional and translational research

Abstract Biomedical research has entered a period of renewed vigor with the introduction and rapid development of genomic technologies and next-generation sequencing methods. This research paradigm produces extremely large datasets that are both difficult to store and challenging to mine for relevant data. Additionally, the thorough exploration of such datasets requires more resources, personnel, and multidisciplinary expertise to properly analyze and interpret the data. As a result, modern biomedical research practices are increasingly designed to include multi-laboratory collaborations that effectively distribute the scientific workload and expand the pool of expertise within a project. The scope of biomedical research is further complicated by increased efforts in translational research, which mandates the translation of basic laboratory research results into the human medical application space, adding to the complexity of potential collaborations. This increase in multidisciplinary, multi-laboratory, and biomedical translational research identifies a specific need for formalized collaboration practices and software applications that support such efforts. Here, we describe formal technological requirements for such efforts and we review several software solutions that can effectively improve the organization, communication, and formalization of collaborations in biomedical research today.</p

Expression profiling in alcoholism research

This article represents the proceedings of a symposium at the 2004 International Society for Biomedical Research on Alcoholism in Mannheim, Germany, organized and co-chaired by Susan E. Bergeson and Wolfgang Sommer. The presentations and presenter were (1) Gene Expression in Brains of AlcoholPreferring and Non-Preferring Rats, by Howard J. Edenberg (2) Candidate Treatment Targets for Alcoholism: Leads from Functional Genomics Approaches, by Wolfgang Sommer (3) Microarray Analysis of Acute and Chronic Alcohol Response in Brain, by Susan E. Bergeson (4) On the Integration of QTL and Gene Expression Analysis, by Robert J. Hitzemann (5) Microarray and Proteomic Analysis of the Human Alcoholic Brain, by Peter R. Dodd