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Veena Theendakara, Clare A Peters-Libeu, Dale E Bredesen, Rammohan V Rao
The major genetic risk factor for sporadic Alzheimer's disease (AD) is the lipid binding and transporting carrier protein apolipoprotein E, epsilon 4 allele (ApoE4). One of the unsolved mysteries of AD is how the presence of ApoE4 elicits this age-associated, currently incurable neurodegenerative disease. Recently, we showed that ApoE4 acts as a transcription factor and binds to the promoters of genes involved in a range of processes linked to aging and AD disease pathogenesis. These findings point to novel therapeutic strategies for AD and aging, resulting in an extension of human healthspan, the disease-free and functional period of life...
September 6, 2017: Molecular Neurobiology
Veena Theendakara, Dale E Bredesen, Rammohan V Rao
The apolipoprotein E ε4 allele is the single most important genetic risk factor associated with Alzheimer's disease (AD). Tau phosphorylation and hyperphosphorylation is an underlying feature of AD and is regulated by specific kinases and phosphatases. Among phosphatases, protein phosphatase 2A (PP2A) is the principal tau dephosphorylating enzyme in the brain. Several abnormalities of PP2A have been reported in AD, including among others decreased protein levels of PP2A, decreased mRNA and protein levels of the catalytic subunit PP2AC and variable regulatory B subunits and reduced methylation of the catalytic subunit, all of which results in disruption of the PP2A phosphatase activity...
September 2017: Molecular and Cellular Neurosciences
Karen S Poksay, Douglas J Sheffler, Patricia Spilman, Jesus Campagna, Barbara Jagodzinska, Olivier Descamps, Olivia Gorostiza, Alex Matalis, Michael Mullenix, Dale E Bredesen, Nicholas D P Cosford, Varghese John
Alzheimer's disease (AD) is characterized by neuronal and synaptic loss. One process that could contribute to this loss is the intracellular caspase cleavage of the amyloid precursor protein (APP) resulting in release of the toxic C-terminal 31-amino acid peptide APP-C31 along with the production of APPΔC31, full-length APP minus the C-terminal 31 amino acids. We previously found that a mutation in APP that prevents this caspase cleavage ameliorated synaptic loss and cognitive impairment in a murine AD model...
2017: Frontiers in Pharmacology
Dale E Bredesen, Rammohan V Rao
Alzheimer's disease (AD) is an age-associated, progressive neurodegenerative disease that is characterized by severe memory loss, personality changes, and an overall decline in cognitive function. The cause of AD is not yet completely defined and efforts to find a cure for it have so far been disappointing. AD is one of the most significant health care problems nationally and globally. Recently, we described a personalized therapeutic approach called metabolic enhancement for neurodegeneration (MEND) that successfully reversed the cognitive decline in patients with early AD...
May 2017: Alternative Therapies in Health and Medicine
Sam Famenini, Elizabeth A Rigali, Henry M Olivera-Perez, Johnny Dang, Michael To Chang, Ramesh Halder, Rammohan V Rao, Matteo Pellegrini, Verna Porter, Dale Bredesen, Milan Fiala
Monocyte/macrophages of patients with mild cognitive impairment (MCI) and Alzheimer disease (AD) are defective in phagocytosis and degradation amyloid β1-42 (Aβ1-42), but are improved by ω-3 fatty acids (ω-3s). The hypothesis of this study was that active Aβ1-42 phagocytosis by macrophages prevents brain amyloidosis and thus maintains cognition. We studied the effects of self-supplementation with a drink with ω-3s, antioxidants, and resveratrol on Mini-Mental State Examination (MMSE) scores, macrophage M1M2 phenotype [the ratio of inflammatory cluster of differentiation (CD)54+CD80 and proresolution markers CD163+CD206], and Aβ1-42 phagocytosis in patients initially diagnosed as having MCI or subjective cognitive impairment (SCI)...
January 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Rahul Anantharaman, Thijs Peters, Wen Xing, Marie-Laure Fontaine, Rune Bredesen
Dual phase membranes are highly CO2-selective membranes with an operating temperature above 400 °C. The focus of this work is to quantify the potential of dual phase membranes in pre- and post-combustion CO2 capture processes. The process evaluations show that the dual phase membranes integrated with an NGCC power plant for CO2 capture are not competitive with the MEA process for post-combustion capture. However, dual phase membrane concepts outperform the reference Selexol technology for pre-combustion CO2 capture in an IGCC process...
October 20, 2016: Faraday Discussions
Dale E Bredesen, Edwin C Amos, Jonathan Canick, Mary Ackerley, Cyrus Raji, Milan Fiala, Jamila Ahdidan
Alzheimer's disease is one of the most significant healthcare problems nationally and globally. Recently, the first description of the reversal of cognitive decline in patients with early Alzheimer's disease or its precursors, MCI (mild cognitive impairment) and SCI (subjective cognitive impairment), was published [1]. The therapeutic approach used was programmatic and personalized rather than monotherapeutic and invariant, and was dubbed metabolic enhancement for neurodegeneration (MEND). Patients who had had to discontinue work were able to return to work, and those struggling at work were able to improve their performance...
June 2016: Aging
Ida Marie Bredesen, Karen Bjøro, Lena Gunningberg, Dag Hofoss
BACKGROUND: Pressure ulcers (PUs) are a problem in health care. Staff competency is paramount to PU prevention. Education is essential to increase skills in pressure ulcer classification and risk assessment. Currently, no pressure ulcer learning programs are available in Norwegian. OBJECTIVES: Develop and test an e-learning program for assessment of pressure ulcer risk and pressure ulcer classification. METHODS: HASH(0x46d2e88) DESIGN, PARTICIPANTS AND SETTING: Forty-four nurses working in acute care hospital wards or nursing homes participated and were assigned randomly into two groups: an e-learning program group (intervention) and a traditional classroom lecture group (control)...
May 2016: Nurse Education Today
Patricia R Spilman, Veronique Corset, Olivia Gorostiza, Karen S Poksay, Veronica Galvan, Junli Zhang, Rammohan Rao, Clare Peters-Libeu, Jon Vincelette, Andrew McGeehan, Melita Dvorak-Ewell, Janine Beyer, Jesus Campagna, Krystof Bankiewicz, Patrick Mehlen, Varghese John, Dale E Bredesen
Recent studies have shown that inoculation of susceptible mice with amyloid-β (Aβ) peptides accelerates Aβ deposition in the brain, supporting the idea that Aβ may be self-amplifying; however, the exact mechanism is not understood. Here we provide evidence that Aβ may self-amplify, in part, by inhibiting α-secretase ADAM10 (a disintegrin and metalloprotease) cleavage of full-length Aβ precursor protein (FL AβPP) and therefore allow greater β-secretase processing, and that Aβ itself is a substrate for ADAM10...
March 8, 2016: Journal of Alzheimer's Disease: JAD
Dale E Bredesen
Alzheimer's disease is one of the most significant healthcare problems today, with a dire need for effective treatment. Identifying subtypes of Alzheimer's disease may aid in the development of therapeutics, and recently three different subtypes have been described: type 1 (inflammatory), type 2 (non-inflammatory or atrophic), and type 3 (cortical). Here I report that type 3 Alzheimer's disease is the result of exposure to specific toxins, and is most commonly inhalational (IAD), a phenotypic manifestation of chronic inflammatory response syndrome (CIRS), due to biotoxins such as mycotoxins...
February 2016: Aging
Veena Theendakara, Clare A Peters-Libeu, Patricia Spilman, Karen S Poksay, Dale E Bredesen, Rammohan V Rao
A major unanswered question in biology and medicine is the mechanism by which the product of the apolipoprotein E ε4 allele, the lipid-binding protein apolipoprotein E4 (ApoE4), plays a pivotal role in processes as disparate as Alzheimer's disease (AD; in which it is the single most important genetic risk factor), atherosclerotic cardiovascular disease, Lewy body dementia, hominid evolution, and inflammation. Using a combination of neural cell lines, skin fibroblasts from AD patients, and ApoE targeted replacement mouse brains, we show in the present report that ApoE4 undergoes nuclear translocation, binds double-stranded DNA with high affinity (low nanomolar), and functions as a transcription factor...
January 20, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Craig Gustafson
No abstract text is available yet for this article.
October 2015: Integrative Medicine
Dale E Bredesen
The cause of Alzheimer's disease is incompletely defined, and no truly effective therapy exists. However, multiple studies have implicated metabolic abnormalities such as insulin resistance, hormonal deficiencies, and hyperhomocysteinemia. Optimizing metabolic parameters in a comprehensive way has yielded cognitive improvement, both in symptomatic and asymptomatic individuals. Therefore, expanding the standard laboratory evaluation in patients with dementia may be revealing. Here I report that metabolic profiling reveals three Alzheimer's disease subtypes...
August 2015: Aging
C A Raji, H Eyre, S H Wei, D E Bredesen, S Moylan, M Law, G Small, P M Thompson, R M Friedlander, D H Silverman, B T Baune, T A Hoang, N Salamon, A W Toga, M W Vernooij
Preventive neuroradiology is a new concept supported by growing literature. The main rationale of preventive neuroradiology is the application of multimodal brain imaging toward early and subclinical detection of brain disease and subsequent preventive actions through identification of modifiable risk factors. An insightful example of this is in the area of age-related cognitive decline, mild cognitive impairment, and dementia with potentially modifiable risk factors such as obesity, diet, sleep, hypertension, diabetes, depression, supplementation, smoking, and physical activity...
October 2015: AJNR. American Journal of Neuroradiology
Alexei Kurakin, Dale E Bredesen
We applied a self-guiding evolutionary algorithm to initiate the synthesis of the Alzheimer's disease-related data and literature. A protein interaction network associated with amyloid-beta precursor protein (APP) and a seed model that treats Alzheimer's disease as progressive dysregulation of APP-associated signaling were used as dynamic "guides" and structural "filters" in the recursive search, analysis, and assimilation of data to drive the evolution of the seed model in size, detail, and complexity. Analysis of data and literature across sub-disciplines and system-scale discovery platforms suggests a key role of dynamic cytoskeletal connectivity in the stability, plasticity, and performance of multicellular networks and architectures...
June 10, 2015: Oncotarget
Milan Fiala, Ramesh C Halder, Bien Sagong, Olivia Ross, James Sayre, Verna Porter, Dale E Bredesen
We investigated the effects of 4-17 month supplementation with ω-3 fatty acids and antioxidants (Smartfish drink; Smartfish AS, Oslo, Norway) in 12 patients with minor cognitive impairment (MCI) [minimental state examination (MMSE) ≥19], 2 patients with pre-MCI (normal MMSE), and 7 patients with Alzheimer disease (AD) (MMSE <19). We measured the phagocytosis of amyloid-β 1-42 (Aβ) by flow cytometry and microscopy, the transcription of inflammatory genes by RT-PCR, the production of resolvin D1 (RvD1) by enzyme immunoassay, and the cognitive status by MMSE...
July 2015: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
H Michael Ellerby, Dale E Bredesen, Satoshi Fujimura, Varghese John
No abstract text is available yet for this article.
February 26, 2015: Journal of Medicinal Chemistry
Ida Marie Bredesen, Karen Bjøro, Lena Gunningberg, Dag Hofoss
BACKGROUND: Pressure ulcers are preventable adverse events. Organizational differences may influence the quality of prevention across wards and hospitals. OBJECTIVE: To investigate the prevalence of pressure ulcers, patient-related risk factors, the use of preventive measures and how much of the pressure ulcer variance is at patient, ward and hospital level. DESIGN: A cross-sectional study. SETTING: Six of the 11 invited hospitals in South-Eastern Norway agreed to participate...
January 2015: International Journal of Nursing Studies
Dale E Bredesen
This report describes a novel, comprehensive, and personalized therapeutic program that is based on the underlying pathogenesis of Alzheimer's disease, and which involves multiple modalities designed to achieve metabolic enhancement for neurodegeneration (MEND). The first 10 patients who have utilized this program include patients with memory loss associated with Alzheimer's disease (AD), amnestic mild cognitive impairment (aMCI), or subjective cognitive impairment (SCI). Nine of the 10 displayed subjective or objective improvement in cognition beginning within 3-6 months, with the one failure being a patient with very late stage AD...
September 2014: Aging
L Galluzzi, J M Bravo-San Pedro, I Vitale, S A Aaronson, J M Abrams, D Adam, E S Alnemri, L Altucci, D Andrews, M Annicchiarico-Petruzzelli, E H Baehrecke, N G Bazan, M J Bertrand, K Bianchi, M V Blagosklonny, K Blomgren, C Borner, D E Bredesen, C Brenner, M Campanella, E Candi, F Cecconi, F K Chan, N S Chandel, E H Cheng, J E Chipuk, J A Cidlowski, A Ciechanover, T M Dawson, V L Dawson, V De Laurenzi, R De Maria, K-M Debatin, N Di Daniele, V M Dixit, B D Dynlacht, W S El-Deiry, G M Fimia, R A Flavell, S Fulda, C Garrido, M-L Gougeon, D R Green, H Gronemeyer, G Hajnoczky, J M Hardwick, M O Hengartner, H Ichijo, B Joseph, P J Jost, T Kaufmann, O Kepp, D J Klionsky, R A Knight, S Kumar, J J Lemasters, B Levine, A Linkermann, S A Lipton, R A Lockshin, C López-Otín, E Lugli, F Madeo, W Malorni, J-C Marine, S J Martin, J-C Martinou, J P Medema, P Meier, S Melino, N Mizushima, U Moll, C Muñoz-Pinedo, G Nuñez, A Oberst, T Panaretakis, J M Penninger, M E Peter, M Piacentini, P Pinton, J H Prehn, H Puthalakath, G A Rabinovich, K S Ravichandran, R Rizzuto, C M Rodrigues, D C Rubinsztein, T Rudel, Y Shi, H-U Simon, B R Stockwell, G Szabadkai, S W Tait, H L Tang, N Tavernarakis, Y Tsujimoto, T Vanden Berghe, P Vandenabeele, A Villunger, E F Wagner, H Walczak, E White, W G Wood, J Yuan, Z Zakeri, B Zhivotovsky, G Melino, G Kroemer
Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as 'accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. 'Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail...
January 2015: Cell Death and Differentiation
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