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Alzheimer's Drug Race: Roche Ramps Up Drug Trial As Rivals Stumble - Huffington Post

My MoinfoAlzheimer's Drug Race: Roche Ramps Up Drug Trial As Rivals StumbleHuffington PostThe failure of rival antibody drugs bapineuzumab, from Pfizer Inc, Johnson & Johnson and Elan Corp , and solanezumab, from Eli Lilly and Co, has dashed hopes...
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Alzheimer's Disease R&D Review
A review of the Solanezumab (Lilly), Gantenerumab (Roche) the 2  beta amyloid monoclonal antibodies  in Phase III trials and other potential targets is provided. The failure of Bapineuzumab in Phase III trials in 2012 puta question mark on the validity of beta amyloid hypothesis. Bapineuzumab is a fully humanized monoclonal antibody which targets beta amyloid protein involved in Alzheimer's Disease. There are 26 million patients in the world, half in Asia and the rest in N America/Europe with AD.
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Created public version #237 of the knol: "Bapineuzumab (Pfizer, J&J, Elan) Review"

Created public version #237 of the knol: "Bapineuzumab (Pfizer, J&J, Elan) Review" | Alzheimer's Disease R&D Review | Scoop.it
Krishan Maggon published version 237 of a knol titled: "Bapineuzumab (Pfizer, J&J, Elan) Review"...
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Alzheimer's research takes a leaf from the prion notebook - Nature.com

Alzheimer's research takes a leaf from the prion notebook - Nature.com | Alzheimer's Disease R&D Review | Scoop.it
Study of rare protein-folding diseases offers tools for examining how amyloid plaques form.

 

At the Colorado meeting, Walker presented a case study of a person with Alzheimer’s disease whose brain was found on post-mortem examination to be riddled with amyloid-β plaques, as expected. Yet the plaques were surprisingly insensitive to a diagnostic imaging molecule that is typically used to detect them. By taking advantage of luminescent compounds that have been used to isolate prions, Walker showed that the patient’s protein aggregates had an unusual architecture that made them invisible to the diagnostic technique. Other research groups are gathering evidence for amyloid-β strains using nuclear magnetic resonance techniques, or applying prion assays to probe whether different strains of tau exist.

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Alzheimer’s research takes a leaf from the prion notebook

Study of rare protein-folding diseases offers tools for examining how amyloid plaques form.

Boer Deng29 May 2015 Nature doi:10.1038/nature.2015.17654
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Researchers clarify role of genetic risk factor in Alzheimer's - USC News

Researchers clarify role of genetic risk factor in Alzheimer's - USC News | Alzheimer's Disease R&D Review | Scoop.it
The study sheds light on potential therapeutic targets for treatment of the disease.

 

Scientists at the Keck School of Medicine of USC have discovered that a protein known as PICALM regulates removal of toxic plaques from the brain, which could be a potential therapeutic target for the treatment of Alzheimer’s disease.

In a study that appeared in a recent edition of Nature Neuroscience, researchers identify this new role for PICALM, which is a known genetic risk factor for Alzheimer’s disease.

 

The study found that a deficiency in PICALM in cerebral blood vessels and in PICALM-related gene variants associated with increased risk for Alzheimer’s, disable amyloid-beta from being cleared out of the brain across a region known as the blood-brain barrier.

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Membrane-Derived Phospholipids Control Synaptic Neurotransmission and Plasticity

Membrane-Derived Phospholipids Control Synaptic Neurotransmission and Plasticity | Alzheimer's Disease R&D Review | Scoop.it
Abstract

Synaptic communication is a dynamic process that is key to the regulation of neuronal excitability and information processing in the brain. To date, however, the molecular signals controlling synaptic dynamics have been poorly understood. Membrane-derived bioactive phospholipids are potential candidates to control short-term tuning of synaptic signaling, a plastic event essential for information processing at both the cellular and neuronal network levels in the brain. Here, we showed that phospholipids affect excitatory and inhibitory neurotransmission by different degrees, loci, and mechanisms of action. Signaling triggered by lysophosphatidic acid (LPA) evoked rapid and reversible depression of excitatory and inhibitory postsynaptic currents. At excitatory synapses, LPA-induced depression depended on LPA1/Gαi/o-protein/phospholipase C/myosin light chain kinase cascade at the presynaptic site. LPA increased myosin light chain phosphorylation, which is known to trigger actomyosin contraction, and reduced the number of synaptic vesicles docked to active zones in excitatory boutons. At inhibitory synapses, postsynaptic LPA signaling led to dephosphorylation, and internalization of the GABAAγ2 subunit through the LPA1/Gα12/13-protein/RhoA/Rho kinase/calcineurin pathway. However, LPA-induced depression of GABAergic transmission was correlated with an endocytosis-independent reduction of GABAA receptors, possibly by GABAAγ2 dephosphorylation and subsequent increased lateral diffusion. Furthermore, endogenous LPA signaling, mainly via LPA1, mediated activity-dependent inhibitory depression in a model of experimental synaptic plasticity. Finally, LPA signaling, most likely restraining the excitatory drive incoming to motoneurons, regulated performance of motor output commands, a basic brain processing task. We propose that lysophospholipids serve as potential local messengers that tune synaptic strength to precedent activity of the neuron.

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Citation: García-Morales V, Montero F, González-Forero D, Rodríguez-Bey G, Gómez-Pérez L, Medialdea-Wandossell MJ, et al. (2015) Membrane-Derived Phospholipids Control Synaptic Neurotransmission and Plasticity. PLoS Biol 13(5): e1002153. doi:10.1371/journal.pbio.1002153

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Aphios alpha (α)-secretase modulator APH-1104 for Alzheimer's disease

Aphios alpha (α)-secretase modulator APH-1104 for Alzheimer's disease | Alzheimer's Disease R&D Review | Scoop.it

Alpha (α)-secretase is another enzyme in the neuronal pathway that positively influences amyloid precursor protein, ('APP') processing. Both β-secretase and γ-secretase cleave APP to form insoluble amyloid plaques (Aβ) that set in motion tau fiber assembly. In contrast, α-secretase cleaves APP into the harmless and more soluble product, 'sAPP-α', that actually supports new synapse formation and is more readily cleared from the brain. Thus, unlike current strategies which aim to suppress Aβ plaque formation by minimizing β- and γ-secretase activities, our strategy to activate α-secretase effectively eliminates the substrate for β- amyloid generation, and at the same time leads to positive amyloid precursor processing to both prevent and reduce Aβ plaques in AD.

APH-1104, a Novel α-Secretase Modulator and Potential AD TherapeuticAphios is developing APH-1104, a more potent analog of Bryostatin-1, which is neuroprotective by α-secretase activation via novel PKC isoforms, down-regulation of pro-inflammatory and angiogenic processes and the substitution of β-amyloid for its soluble and harmless relative, s-APPα. Aphios has successfully developed and patented efficient methods for manufacturing and formulating APH-1104. In 2008, Aphios investigated APH-0703, a less potent analog of APH-1104, as an intravenous formulation for Alzheimer's disease in an open label n=1 clinical trial in the Bahamas. Although limited, the preliminary results of this exploratory study were striking and encouraging.

Krishan Maggon 's insight:

Current research in AD prophylaxis and therapy is centered on identification of methods to decrease Beta amyloid (Aβ) and the assembly of tau tangles, biochemical 'signatures' of AD which are the basis cognitive decline. Beta (β)-secretase inhibitors have been extensively investigated, but have been difficult to translate into effective clinical treatments for AD. A recent Phase II AD clinical trial with the β-secretase inhibitor, LY2886721, was even halted because of liver toxicity. Gamma (γ)-secretase inhibitors may conceivably also reduce Aβ accumulation. However, a recent Phase III clinical trial with the γ-secretase inhibitor, 'Semagacestat' (LY-450139), was also halted because of evidence for accelerated AD dementia. Most of the recent clinical AD trial failures have been with β- and γ-secretase inhibitors.

 

We will develop APH-1104 as a therapeutic for mild to moderate Alzheimer's disease (AD) and cognitive disorders (CD). We plan to utilize other analogs of APH-0703 as backups for APH-1104. Our milestones are as follows: (1) establish cGMP for the API and FDP at the pilot-scale level; (2) establish a drug master file, design IND enabling preclinical studies and Phase I/IIa clinical trials, and draft IND package; (3) conduct FDA-necessary IND-enabling preclinical in vivo studies, including toxicology, efficacy and pharmacology, under GLP; (4) perform stability testing of API and FDP under GLP; (5) file IND for conducting Phase I/IIa clinical trial of APH-1104; and (6) conduct Phase I and IIa clinical trials of oral APH-1104.

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University of Oslo researchers confirm new mechanism for Alzheimer's disease - Medical Xpress

University of Oslo researchers confirm new mechanism for Alzheimer's disease - Medical Xpress | Alzheimer's Disease R&D Review | Scoop.it
Jens Pahnke and his team at the University of Oslo has recently published results in the prestigious scientific journal Brain showing that decreased removal of toxic peptides in the brain causes the onset and first clinical signs of Alzheimer's...

 

Summary

Amyloidosis mouse models of Alzheimer’s disease are generally established by transgenic approaches leading to an overexpression of mutated human genes that are known to be involved in the generation of amyloid-β in Alzheimer’s families. Although these models made substantial contributions to the current knowledge about the ‘amyloid hypothesis’ of Alzheimer’s disease, the overproduction of amyloid-β peptides mimics only inherited (familiar) Alzheimer’s disease, which accounts for <1% of all patients with Alzheimer’s disease. The inherited form is even regarded a ‘rare’ disease according to the regulations for funding of the European Union (www.erare.eu). Here, we show that mice that are double-deficient for neprilysin (encoded by Mme), one major amyloid-β-degrading enzyme, and the ABC transporter ABCC1, a major contributor to amyloid-β clearance from the brain, develop various aspects of sporadic Alzheimer’s disease mimicking the clinical stage of mild cognitive impairment. Using behavioural tests, electrophysiology and morphological analyses, we compared different ABC transporter-deficient animals and found that alterations are most prominent in neprilysin × ABCC1 double-deficient mice. We show that these mice have a reduced probability to survive, show increased anxiety in new environments, and have a reduced working memory performance. Furthermore, we detected morphological changes in the hippocampus and amygdala, e.g. astrogliosis and reduced numbers of synapses, leading to defective long-term potentiation in functional measurements. Compared to human, murine amyloid-β is poorly aggregating, due to changes in three amino acids at N-terminal positions 5, 10, and 13. Interestingly, our findings account for the action of early occurring amyloid-β species/aggregates, i.e. monomers and small amyloid-β oligomers. Thus, neprilysin × ABCC1 double-deficient mice present a new model for early effects of amyloid-β-related mild cognitive impairment that allows investigations without artificial overexpression of inherited Alzheimer’s disease genes.

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Accumulation of murine amyloid-β mimics early Alzheimer’s disease

 

Markus Krohn , Alexander Bracke , Yosef Avchalumov , Toni Schumacher , Jacqueline Hofrichter , Kristin Paarmann , Christina Fröhlich, Cathleen Lange , Thomas Brüning , Oliver von Bohlen und Halbach , Jens PahnkeDOI: http://dx.doi.org/10.1093/brain/awv137 First published online: 19 May 2015

 

 "Accumulation of murine amyloid-{beta} mimics early Alzheimer's disease." Brain 2015; DOI: 10.1093/brain/awv137

Journal reference: Brain

Provided by University of Oslo

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Masitinib for the treatment of mild to moderate Alzheimer’s disease, Expert Review of Neurotherapeutics, Informa Healthcare

Masitinib for the treatment of mild to moderate Alzheimer’s disease, Expert Review of Neurotherapeutics, Informa Healthcare | Alzheimer's Disease R&D Review | Scoop.it

Alzheimer’s disease (AD) is a degenerative neurological disorder that is the most common cause of dementia and disability in older patients. Available treatments are symptomatic in nature and are only sufficient to improve the quality of life of AD patients temporarily. A potential strategy, currently under investigation, is to target cell-signaling pathways associated with neurodegeneration, in order to decrease neuroinflammation, excitotoxicity, and to improve cognitive functions. Current review centers on the role of neuroinflammation and the specific contribution of mast cells to AD pathophysiology. The authors look at masitinib therapy and the evidence presented through preclinical and clinical trials. Dual actions of masitinib as an inhibitor of mast cell–glia axis and a Fyn kinase blocker are discussed in the context of AD pathology. Masitinib is in Phase III clinical trials for the treatment of malignant melanoma, mastocytosis, multiple myeloma, gastrointestinal cancer and pancreatic cancer. It is also in Phase II/III clinical trials for the treatment of multiple sclerosis, rheumatoid arthritis and AD. Additional research is warranted to better investigate the potential effects of masitinib in combination with other drugs employed in AD treatment.


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With the involvement of multiple signaling cascades, it is quite possible that a single drug could target more than one pathway. Such is the case of masitinib, a TKI which is capable of both c-kit and Fyn inhibition. Masitinib, in combination with other disease-modifying compounds, could be instrumental in improving dendritic integrity in memory circuits. Dual actions of masitinib may lead to improvements in synaptic plasticity in patients with mild to moderate forms of AD.

 

Masitinib for the treatment of mild to moderate Alzheimer’s disease

 

Posted online on May 11, 2015. (doi:10.1586/14737175.2015.1045419)HTMLPDF (504 KB)PDF Plus (510 KB)ReprintsPermissionsJaume Folch, Dmitry Petrov, Miren Ettecho, Ignacio Pedrós, Sonia Abad, Carlos Beas-Zarate, Alberto Lazarowski, Miguel Marin, Jordi Olloquequi, Carme Auladell, and Antoni Camins




Read More: http://informahealthcare.com/doi/abs/10.1586/14737175.2015.1045419

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Hairy/Enhancer-of-Split MEGANE and Proneural MASH1 Factors Cooperate Synergistically in Midbrain GABAergic Neurogenesis

Hairy/Enhancer-of-Split MEGANE and Proneural MASH1 Factors Cooperate Synergistically in Midbrain GABAergic Neurogenesis | Alzheimer's Disease R&D Review | Scoop.it
GABAergic neurons are the primary inhibitory cell type in the mature brain and their dysfunction is associated with important neurological conditions like schizophrenia and anxiety. We aimed to discover the underlying mechanisms for dorsal/ventral midbrain GABAergic neurogenesis. Previous work by us and others has provided crucial insights into the key function of Mgn and Mash1 genes in determining GABAergic neurotransmitter fate. Induction of dorsal midbrain GABAergic neurons does not take place at any time during development in either of the single mutant mice. However, GABAergic neurons in the ventral midbrain remained unchanged. Thus, the similarities in MB-GABAergic phenotype observed in the Mgn and Mash1 single mutants suggest the existence of other factors that take over the function of MGN and MASH1 in the ventral midbrain or the existence of different molecular mechanisms. We show that this process essentially depends on heterodimers and homodimers formed by MGN and MASH1 and deciphered the in vivo relevance of the interaction by phenotypic analysis of Mgn/Mash1 double knockout and compound mice. Furthermore, the combination of gain- and loss-of-function experiments in the developing midbrain showed co-operative roles for Mgn and Mash1 genes in determining GABAergic identity. Transcription factors belonging to the Enhancer-of-split-related and proneural families have long been believed to counterpart each other’s function. This work uncovers a synergistic cooperation between these two families, and provides a novel paradigm for how these two families cooperate for the acquisition of MB-GABAergic neuronal identity. Understanding their molecular mechanisms is essential for cell therapy strategies to amend GABAergic deficits.
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Citation: Wende C-Z, Zoubaa S, Blak A, Echevarria D, Martinez S, Guillemot F, et al. (2015) Hairy/Enhancer-of-Split MEGANE and Proneural MASH1 Factors Cooperate Synergistically in Midbrain GABAergic Neurogenesis. PLoS ONE 10(5): e0127681. doi:10.1371/journal.pone.0127681

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Neurotransmitter and psychostimulant recognition by the dopamine transporter

Neurotransmitter and psychostimulant recognition by the dopamine transporter | Alzheimer's Disease R&D Review | Scoop.it

Na+/Cl–-coupled biogenic amine transporters are the primary targets of therapeutic and abused drugs, ranging from antidepressants to the psychostimulants cocaine and amphetamines, and to their cognate substrates. Here we determine X-ray crystal structures of the Drosophila melanogaster dopamine transporter (dDAT) bound to its substrate dopamine, a substrate analogue 3,4-dichlorophenethylamine, the psychostimulants D-amphetamine and methamphetamine, or to cocaine and cocaine analogues. All ligands bind to the central binding site, located approximately halfway across the membrane bilayer, in close proximity to bound sodium and chloride ions. The central binding site recognizes three chemically distinct classes of ligands via conformational changes that accommodate varying sizes and shapes, thus illustrating molecular principles that distinguish substrates from inhibitors in biogenic amine transporters.

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NATURE | ARTICLE

Neurotransmitter and psychostimulant recognition by the dopamine transporterKevin H. Wang,Aravind Penmatsa& Eric GouauxAffiliationsContributionsCorresponding authorNature 521, 322–327 (21 May 2015) doi:10.1038/nature14431Received 06 November 2014 Accepted 23 March 2015 Published online 11 May 2015Article tools

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2015 Alzheimer's disease facts and figures - Alzheimer's & Dementia: The Journal of the Alzheimer's Association

2015 Alzheimer's disease facts and figures - Alzheimer's & Dementia: The Journal of the Alzheimer's Association | Alzheimer's Disease R&D Review | Scoop.it
Abstract

This report discusses the public health impact of Alzheimer's disease (AD), including incidence and prevalence, mortality rates, costs of care and the overall effect on caregivers and society. It also examines the challenges encountered by health care providers when disclosing an AD diagnosis to patients and caregivers. An estimated 5.3 million Americans have AD; 5.1 million are age ≥65 years, and approximately 200,000 are age <65 years and have younger onset AD. By mid-century, the number of people living with AD in the United States is projected to grow by nearly 10 million, fueled in large part by the aging baby boom generation. Today, someone in the country develops AD every 67 seconds. By 2050, one new case of AD is expected to develop every 33 seconds, resulting in nearly 1 million new cases per year, and the estimated prevalence is expected to range from 11 million to 16 million. In 2013, official death certificates recorded 84,767 deaths from AD, making AD the sixth leading cause of death in the United States and the fifth leading cause of death in Americans age ≥65 years. Between 2000 and 2013, deaths resulting from heart disease, stroke and prostate cancer decreased 14%, 23% and 11%, respectively, whereas deaths from AD increased 71%. The actual number of deaths to which AD contributes (or deaths with AD) is likely much larger than the number of deaths from AD recorded on death certificates. In 2015, an estimated 700,000 Americans age ≥65 years will die with AD, and many of them will die from complications caused by AD. In 2014, more than 15 million family members and other unpaid caregivers provided an estimated 17.9 billion hours of care to people with AD and other dementias, a contribution valued at more than $217 billion. Average per-person Medicare payments for services to beneficiaries age ≥65 years with AD and other dementias are more than two and a half times as great as payments for all beneficiaries without these conditions, and Medicaid payments are 19 times as great. Total payments in 2015 for health care, long-term care and hospice services for people age ≥65 years with dementia are expected to be $226 billion. Among people with a diagnosis of AD or another dementia, fewer than half report having been told of the diagnosis by their health care provider. Though the benefits of a prompt, clear and accurate disclosure of an AD diagnosis are recognized by the medical profession, improvements to the disclosure process are needed. These improvements may require stronger support systems for health care providers and their patients.

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March 2015Volume 11, Issue 3, Pages 332–3842015 Alzheimer's disease facts and figuresAlzheimer's Association*DOI: http://dx.doi.org/10.1016/j.jalz.2015.02.003 Article Info
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Prevalence of Cerebral Amyloid Pathology in Persons Without Dementia

Prevalence of Cerebral Amyloid Pathology in Persons Without Dementia | Alzheimer's Disease R&D Review | Scoop.it
This meta-analysis explores the association of amyloid pathology with age, APOE genotype, sex, education, and presence of cognitive impairment among persons without dementia.

 

Results  The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality.

Conclusions and Relevance  Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.

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Prevalence of Cerebral Amyloid Pathology in Persons Without DementiaA Meta-analysisWillemijn J. Jansen, MSc1; Rik Ossenkoppele, PhD2,3,4,5; Dirk L. Knol, PhD6; Betty M. Tijms, PhD2; Philip Scheltens, MD, PhD2; Frans R. J. Verhey, MD, PhD1; Pieter Jelle Visser, MD, PhD1,2 ; and the Amyloid Biomarker Study Group[+] Author AffiliationsJAMA. 2015;313(19):1924-1938. doi:10.1001/jama.2015.4668.
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Common genetic variant association with altered HLA expression, synergy with pyrethroid exposure, and risk for Parkinson’s disease: an observational and case–control study

Common genetic variant association with altered HLA expression, synergy with pyrethroid exposure, and risk for Parkinson’s disease: an observational and case–control study | Alzheimer's Disease R&D Review | Scoop.it
npj Parkinson's Disease, Published online: 22 April 2015; | doi:10.1038/npjparkd.2015.2

 

Abstract  Nature Parkinson's Disease

 

Background:

The common noncoding single-nucleotide polymorphism (SNP) rs3129882 in HLA-DRA is associated with risk for idiopathic Parkinson’s disease (PD). The location of the SNP in the major histocompatibility complex class II (MHC-II) locus implicates regulation of antigen presentation as a potential mechanism by which immune responses link genetic susceptibility to environmental factors in conferring lifetime risk for PD.

Aims:

The aim of this study was to determine the effect of this SNP on the MHC-II locus and its synergy with pesticide exposure.

Methods:

For immunophenotyping, blood cells from 81 subjects were analyzed by quantitative reverse transcription-PCR and flow cytometry. A case–control study was performed on a separate cohort of 962 subjects to determine association of pesticide exposure and the SNP with risk of PD.

Results:

Homozygosity for G at this SNP was associated with heightened baseline expression and inducibility of MHC class II molecules in B cells and monocytes from peripheral blood of healthy controls and PD patients. In addition, exposure to a commonly used class of insecticide, pyrethroids, synergized with the risk conferred by this SNP (odds ratio=2.48, P=0.007), thereby identifying a novel gene–environment interaction that promotes risk for PD via alterations in immune responses.

Conclusions:

In sum, these novel findings suggest that the MHC-II locus may increase susceptibility to PD through presentation of pathogenic, immunodominant antigens and/or a shift toward a more pro-inflammatory CD4+ T-cell response in response to specific environmental exposures, such as pyrethroid exposure through genetic or epigenetic mechanisms that modulate MHC-II gene expression.

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Common genetic variant association with altered HLA expression, synergy with pyrethroid exposure, and risk for Parkinson’s disease: an observational and case–control studyG T Kannarkat, D A Cook, J-K Lee, J Chang, J Chung, E Sandy, K C Paul, B Ritz, J Bronstein, S A Factor, J M Boss & M G TanseyAffiliationsCorresponding authorsnpj Parkinson's Disease 1, Article number: 15002 (2015) doi:10.1038/npjparkd.2015.2Received 17 January 2015 Revised 14 March 2015 Accepted 26 March 2015 Published online 22 April 2015
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Improvement of Spatial Memory Disorder and Hippocampal Damage by Exposure to Electromagnetic Fields in an Alzheimer’s Disease Rat Model

Improvement of Spatial Memory Disorder and Hippocampal Damage by Exposure to Electromagnetic Fields in an Alzheimer’s Disease Rat Model | Alzheimer's Disease R&D Review | Scoop.it

by Xiao Liu, Hongyan Zuo, Dewen Wang, Ruiyun Peng, Tao Song, Shuiming Wang, Xinping Xu, Yabing Gao, Yang Li, Shaoxia Wang, Lifeng Wang, Li Zhao 

 

Abstract

 

Although some epidemiological investigations showed a potential association between long-term exposure of extremely low frequency electromagnetic fields (ELF-EMF) and Alzheimer’s disease (AD), no reasonable mechanism can explain this association, and the related animal experiments are rare. In this study, ELF-EMF exposure (50Hz 400µT 60d) combined with D-galactose intraperitoneal (50mg/kg, q.d., 42d) and Aβ25–35 hippocampal (5μl/unilateral, bilateral, single-dose) injection was implemented to establish a complex rat model. Then the effects of ELF-EMF exposure on AD development was studied by using the Morris water maze, pathological analysis, and comparative proteomics. The results showed that ELF-EMF exposure delayed the weight gain of rats, and partially improved cognitive and clinicopathologic symptoms of AD rats. The differential proteomic analysis results suggest that synaptic transmission, oxidative stress, protein degradation, energy metabolism, Tau aggregation, and inflammation involved in the effects mentioned above. Therefore, our findings indicate that certain conditions of ELF-EMF exposure could delay the development of AD in rats.

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Citation: Liu X, Zuo H, Wang D, Peng R, Song T, Wang S, et al. (2015) Improvement of Spatial Memory Disorder and Hippocampal Damage by Exposure to Electromagnetic Fields in an Alzheimer’s Disease Rat Model. PLoS ONE 10(5): e0126963. doi:10.1371/journal.pone.0126963

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Système immunitaire du cerveau

Système immunitaire du cerveau | Alzheimer's Disease R&D Review | Scoop.it

Les oligodendrocytes (beige clair en bas à gauche) contrôlent la gaine de myéline (production et restauration). Les astrocytes en haut à gauche (marron clair) contrôlent directement l'activité nerveuse de l'axone et absorbent les surplus de neuromédiateurs. Les cellules microgliales (en rouge à droite) sont en contact avec les astrocytes et les terminaisons nerveuses des neurones. 

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L'immunothérapie des glioblastomes
Auteurs : Szabo À, Professeur Antoine Carpentier. 
Hôpital Avicenne, 125, avenue de Stalingrad, 75013 Bobigny, France, Université Paris 13, UFR de santé, 74, rue Marcel-Cachin, 93017 Bobigny Cedex, France. 

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L'immunothérapie des glioblastomes
Auteurs : Szabo À, Professeur Antoine Carpentier. 
Hôpital Avicenne, 125, avenue de Stalingrad, 75013 Bobigny, France, Université Paris 13, UFR de santé, 74, rue Marcel-Cachin, 93017 Bobigny Cedex, France. 

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Eight weeks to a better brain

Eight weeks to a better brain | Alzheimer's Disease R&D Review | Scoop.it
Harvard researchers at Massachusetts General Hospital find that participating in an eight-week mindfulness meditation program appears to make measurable changes in brain regions associated with memory, sense of self, empathy, and stress.

Via Jone Johnson Lewis, Alejandro Melo-Florián MD
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MÁS evidencia del impacto positivo de la meditación en el cerebro. #PsicologiaPositiva, #PosPsy

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Imaging Test Might Identify Biomarker of Alzheimer's Disease - Healthline

Imaging Test Might Identify Biomarker of Alzheimer's Disease - Healthline | Alzheimer's Disease R&D Review | Scoop.it
Scientists say deteriorating white matter in the brain could be an early indicator of Alzheimer’s.

 

A study published in Radiology concludes that white matter plays an important role in how the disease strikes and progresses.

Alzheimer’s disease (AD) creates abnormal deposits of proteins that form amyloid plaques and tau tangles throughout the brain. It is also characterized by a loss of neurons, a process that causes brain tissue to shrink.

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Copy Number Variations in Cognitive Phenotypes

Copy Number Variations in Cognitive Phenotypes | Alzheimer's Disease R&D Review | Scoop.it
This population-based study investigated the association of copy number variance and cognitive phenotypes and educational attainment and intellectual disability among individuals whose genetic samples are recorded in the Estonian Genome Center, the...

 

Main Outcomes and Measures  Phenotypes of genomic disorders in the general population, prevalence of autosomal CNVs, and association of these variants with educational attainment (from less than primary school through scientific degree) and prevalence of intellectual disability.

Results  Of the 7877 in the Estonian cohort, we identified 56 carriers of CNVs associated with known syndromes. Their phenotypes, including cognitive and psychiatric problems, epilepsy, neuropathies, obesity, and congenital malformations are similar to those described for carriers of identical rearrangements ascertained in clinical cohorts. A genome-wide evaluation of rare autosomal CNVs (frequency, ≤0.05%; ≥250 kb) identified 831 carriers (10.5%) of the screened general population. Eleven of 216 (5.1%) carriers of a deletion of at least 250 kb (odds ratio [OR], 3.16; 95% CI, 1.51-5.98; P = 1.5e-03) and 6 of 102 (5.9%) carriers of a duplication of at least 1 Mb (OR, 3.67; 95% CI, 1.29-8.54; P = .008) had an intellectual disability compared with 114 of 6819 (1.7%) in the Estonian cohort. The mean education attainment was 3.81 (P = 1.06e-04) among 248 (≥250 kb) deletion carriers and 3.69 (P = 5.024e-05) among 115 duplication carriers (≥1 Mb). Of the deletion carriers, 33.5% did not graduate from high school (OR, 1.48; 95% CI, 1.12-1.95; P = .005) and 39.1% of duplication carriers did not graduate high school (OR, 1.89; 95% CI, 1.27-2.8;P = 1.6e-03). Evidence for an association between rare CNVs and lower educational attainment was supported by analyses of cohorts of adults from Italy and the United States and adolescents from the United Kingdom.

Conclusions and Relevance  Known pathogenic CNVs in unselected, but assumed to be healthy, adult populations may be associated with unrecognized clinical sequelae. Additionally, individually rare but collectively common intermediate-size CNVs may be negatively associated with educational attainment. Replication of these findings in additional population groups is warranted given the potential implications of this observation for genomics research, clinical care, and public health.

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Original Investigation | May 26, 2015Copy Number Variations and Cognitive Phenotypes in Unselected PopulationsKatrin Männik, PhD1,2; Reedik Mägi, PhD2; Aurélien Macé, MSc3,4; Ben Cole, BS5; Anna L. Guyatt, MBChB6; Hashem A. Shihab, PhD6,7; Anne M. Maillard, PhD3; Helene Alavere, MD, MSc2; Anneli Kolk, MD, PhD2,8; Anu Reigo, MD2; Evelin Mihailov, MSc2; Liis Leitsalu, MSc2,9; Anne-Maud Ferreira, MSc1,4; Margit Nõukas, MSc2,9; Alexander Teumer, PhD10; Erika Salvi, PhD11; Daniele Cusi, PhD11,12; Matt McGue, PhD13; William G. Iacono, PhD13; Tom R. Gaunt, PhD6,7; Jacques S. Beckmann, PhD4; Sébastien Jacquemont, MD3; Zoltán Kutalik, PhD3,4,14; Nathan Pankratz, PhD5; Nicholas Timpson, PhD6,7; Andres Metspalu, MD, PhD2,9; Alexandre Reymond, PhD1[+] Author AffiliationsJAMA. 2015;313(20):2044-2054. doi:10.1001/jama.2015.4845.

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Motor Inhibition during Overt and Covert Actions: An Electrical Neuroimaging Study

Given ample evidence for shared cortical structures involved in encoding actions, whether or not subsequently executed, a still unsolved problem is the identification of neural mechanisms of motor inhibition, preventing “covert actions” as motor imagery from being performed, in spite of the activation of the motor system. The principal aims of the present study were the evaluation of: 1) the presence in covert actions as motor imagery of putative motor inhibitory mechanisms; 2) their underlying cerebral sources; 3) their differences or similarities with respect to cerebral networks underpinning the inhibition of overt actions during a Go/NoGo task. For these purposes, we performed a high density EEG study evaluating the cerebral microstates and their related sources elicited during two types of Go/NoGo tasks, requiring the execution or withholding of an overt or a covert imagined action, respectively. Our results show for the first time the engagement during motor imagery of key nodes of a putative inhibitory network (including pre-supplementary motor area and right inferior frontal gyrus) partially overlapping with those activated for the inhibition of an overt action during the overt NoGo condition. At the same time, different patterns of temporal recruitment in these shared neural inhibitory substrates are shown, in accord with the intended overt or covert modality of action performance. The evidence that apparently divergent mechanisms such as controlled inhibition of overt actions and contingent automatic inhibition of covert actions do indeed share partially overlapping neural substrates, further challenges the rigid dichotomy between conscious, explicit, flexible and unconscious, implicit, inflexible forms of motor behavioral control.
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Inside the Brain Unraveling the Mystery of Alzheimer's Disease HQ

Inside the Brain Unraveling the Mystery of Alzheimer's Disease HQ.
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ALK5 A Single Drug Simultaneously Rejuvenates Hippocampal Neurogenesis and Myogenesis In The Same Old Mammal

ALK5 A Single Drug Simultaneously Rejuvenates Hippocampal Neurogenesis and Myogenesis In The Same Old Mammal | Alzheimer's Disease R&D Review | Scoop.it
Systemic attenuation of the TGF-β pathway by a single drug (ALK5) simultaneously rejuvenates hippocampal neurogenesis and myogenesis in the same old mammal

 

Abstract

 

Stem cell function declines with age largely due to the biochemical imbalances in their tissue niches, and this work demonstrates that aging imposes an elevation in transforming growth factor β (TGF-β) signaling in the neurogenic niche of the hippocampus, analogous to the previously demonstrated changes in the myogenic niche of skeletal muscle with age. Exploring the hypothesis that youthful calibration of key signaling pathways may enhance regeneration of multiple old tissues, we found that systemically attenuating TGF-β signaling with a single drug simultaneously enhanced neurogenesis and muscle regeneration in the same old mice, findings further substantiated via genetic perturbations. At the levels of cellular mechanism, our results establish that the age-specific increase in TGF-β1 in the stem cell niches of aged hippocampus involves microglia and that such an increase is pro-inflammatory both in brain and muscle, as assayed by the elevated expression of β2 microglobulin (B2M), a component of MHC class I molecules. These findings suggest that at high levels typical of aged tissues, TGF-β1 promotes inflammation instead of its canonical role in attenuating immune responses. In agreement with this conclusion, inhibition of TGF-β1 signaling normalized B2M to young levels in both studied tissues.

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h+ Magzine

 

Breakthrough Paper: ALK5 Inhibitor A Single Drug Simultaneously Rejuvenates Hippocampal Neurogenesis and Myogenesis In The Same Old MammalMay 21, 2015 Academic Papers, Aging, images, Rejeuvenation By: Hanadie Yousef, Michael J. Conboy1, Adam Morgenthaler, Christina Schlesinger, Lukasz Bugaj, Preeti Paliwal, Christopher Greer, Irina M. Conboy, David Schaffer

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Brain Plaque Forecasts Alzheimer's Years in Advance, Studies Confirm - Drug Discovery & Development

Brain Plaque Forecasts Alzheimer's Years in Advance, Studies Confirm - Drug Discovery & Development | Alzheimer's Disease R&D Review | Scoop.it
Brain plaques may appear up to 30 years prior to developing Alzheimer’s disease, according to the largest analysis to date of beta amyloid in people’s brains.
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Repositioning of Memantine as a Potential Novel Therapeutic Agent against Meningitic E. coli–Induced Pathogenicities through Disease-Associated Alpha7 Cholinergic Pathway and RNA Sequencing-Based T...

Repositioning of Memantine as a Potential Novel Therapeutic Agent against Meningitic E. coli–Induced Pathogenicities through Disease-Associated Alpha7 Cholinergic Pathway and RNA Sequencing-Based T... | Alzheimer's Disease R&D Review | Scoop.it
by Jing-Yi Yu, Bao Zhang, Liang Peng, Chun-Hua Wu, Hong Cao, John F.

 

Abstract

Neonatal sepsis and meningitis (NSM) remains a leading cause worldwide of mortality and morbidity in newborn infants despite the availability of antibiotics over the last several decades.E. coli is the most common gram-negative pathogen causing NSM. Our previous studies show that α7 nicotinic receptor (α7 nAChR), an essential regulator of inflammation, plays a detrimental role in the host defense against NSM. Despite notable successes, there still exists an unmet need for new effective therapeutic approaches to treat this disease. Using the in vitro/in vivo models of the blood-brain barrier (BBB) and RNA-seq, we undertook a drug repositioning study to identify unknown antimicrobial activities for known drugs. We have demonstrated for the first time that memantine (MEM), a FDA-approved drug for treatment of Alzheimer’s disease, could very efficiently block E. coli-caused bacteremia and meningitis in a mouse model of NSM in a manner dependent on α7 nAChR. MEM was able to synergistically enhance the antibacterial activity of ampicillin in HBMEC infected with E. coli K1 (E44) and in neonatal mice with E44-caused bacteremia and meningitis. Differential gene expression analysis of RNA-Seq data from mouse BMEC infected with E. coli K1 showed that several E44-increased inflammatory factors, including IL33, IL18rap, MMP10 and Irs1, were significantly reduced by MEM compared to the infected cells without drug treatment. MEM could also significantly up-regulate anti-inflammatory factors, including Tnfaip3, CISH, Ptgds and Zfp36. Most interestingly, these factors may positively and negatively contribute to regulation of NF-κB, which is a hallmark feature of bacterial meningitis. Furthermore, we have demonstrated that circulating BMEC (cBMEC) are the potential novel biomarkers for NSM. MEM could significantly reduce E44-increased blood level of cBMEC in mice. Taken together, our data suggest that memantine can efficiently block host inflammatory responses to bacterial infection through modulation of both inflammatory and anti-inflammatory pathways.

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Citation: Yu J-Y, Zhang B, Peng L, Wu C-H, Cao H, Zhong JF, et al. (2015) Repositioning of Memantine as a Potential Novel Therapeutic Agent against MeningiticE. coli–Induced Pathogenicities through Disease-Associated Alpha7 Cholinergic Pathway and RNA Sequencing-Based Transcriptome Analysis of Host Inflammatory Responses. PLoS ONE 10(5): e0121911. doi:10.1371/journal.pone.0121911

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Blood Pressure Control and Cognitive Performance

JAMA NeurologyMidlife Hypertension and 20-Year Cognitive Change: The Atherosclerosis Risk in Communities Neurocognitive StudyRebecca F. Gottesman, MD, PhD; Andrea L. C.

 

Results During 20 years, baseline hypertension was associated with an additional decline of 0.056 global z score points (95% CI, −0.100 to −0.012) and prehypertension was associated nonsignificantly with 0.040 more global z score points of decline (95% CI, −0.085 to 0.005) compared with normal BP. Individuals with hypertension who used antihypertensives had less decline during the 20 years than untreated individuals with hypertension (−0.050 [95% CI, −0.003 to −0.097] vs −0.079 [95% CI, −0.156 to −0.002] global z score points). Having a JNC-8–specified indication for initiating antihypertensive treatment at baseline was associated with a greater 20-year decline (−0.044 [95% CI, −0.085 to −0.003] global z score points) than not having an indication. We observed effect modification by race for the continuous systolic BP analyses (P = .01), with each 20–mm Hg increment at baseline associated with an additional decline of 0.048 (95% CI, −0.074 to −0.022) points in global cognitive zscore in whites but not in African Americans (decline, −0.020 [95% CI, −0.026 to 0.066] points). Systolic BP at the end of follow-up was not associated with the preceding 20 years of cognitive change in either group. Methods to account for bias owing to attrition strengthened the magnitude of some associations.

Conclusions and Relevance Midlife hypertension and elevated midlife but not late-life systolic BP was associated with more cognitive decline during the 20 years of the study. Greater decline is found with higher midlife BP in whites than in African Americans.

JAMA Neurol. 2014;71(10):1218-1227. doi:10.1001/jamaneurol.2014.1646

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From the JAMA Network | May 19, 2015Blood Pressure Control and Cognitive PerformanceSomething to Think About With AgingCharles DeCarli, MD1[+] Author AffiliationsJAMA. 2015;313(19):1963-1964. doi:10.1001/jama.2015.3113.
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Prevalence of Positive Amyloid PET Scans in People With Dementia

Prevalence of Positive Amyloid PET Scans in People With Dementia | Alzheimer's Disease R&D Review | Scoop.it
This participant-level meta-analysis estimates the prevalence of PET scan–measured amyloid in Alzheimer disease participants and its associations with age, sex, education, cognitive function, and APOE genotype.

 

Conclusions and Relevance  Among participants with dementia, the prevalence of amyloid positivity was associated with clinical diagnosis, age, and APOE genotype. These findings indicate the potential clinical utility of amyloid imaging for differential diagnosis in early-onset dementia and to support the clinical diagnosis of participants with AD dementia and noncarrier APOE ε4 status who are older than 70 years.

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Prevalence of Amyloid PET Positivity in Dementia SyndromesA Meta-analysisRik Ossenkoppele, PhD1,2,3,4; Willemijn J. Jansen, MSc5; Gil D. Rabinovici, MD3,4; Dirk L. Knol, PhD6; Wiesje M. van der Flier, PhD1,6; Bart N. M. van Berckel, MD, PhD2; Philip Scheltens, MD, PhD1; Pieter Jelle Visser, MD, PhD1,5 ; and the Amyloid PET Study Group[+] Author AffiliationsJAMA. 2015;313(19):1939-1949. doi:10.1001/jama.2015.4669.

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Mayo Clinic Breakthrough With ALS Treatment In Mice - Science Times

Mayo Clinic Breakthrough With ALS Treatment In Mice - Science Times | Alzheimer's Disease R&D Review | Scoop.it
Researchers at the Jacksonville, Florida Mayo Clinic have gained a mouse model for testing potential amyotrophic lateral sclerosis (ALS) treatments.
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Prospecting for drugs in the cerebral minefield - ExtremeTech

Prospecting for drugs in the cerebral minefield - ExtremeTech | Alzheimer's Disease R&D Review | Scoop.it
Companies that make drugs for neurodegenerative disease, like Biogen, are now coming up with ingenious new way to get around the blood brain barrier.
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