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Science 2017-01-25T11:47:44-08:00

The Science Behind The

bredensen_protocol

Reversal of Cognitive Decline in Alzheimer’s Disease

…Dementia is one of the most significant global healthcare problems, with over 30 million symptomatic individuals, and many more likely to be in the decades long, pre-symptomatic phases (World Alzheimer Report, 2009, http://www.alz.co.uk/research/files/WorldAlzheimerReport.pdf). In the United States alone, over five million people suffer from Alzheimer’s disease (AD), at an estimated annual cost of $200 billion, and a projection for 13 million patients by 2050. The high prevalence of AD is of particular concern because of the lack of success in developing effective therapeutics: in comparison to most classes of disease – from neoplasia to cardiovascular and cerebrovascular disease to osteoporosis to diabetes to mental illness – therapeutic development for AD has been, to date, a failure. Why?…

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Next Generation Therapeutics for Alzheimer’s Disease

…Dementia is one of the most significant global healthcare problems, with over 30 million symptomatic individuals, and many more likely to be in the decades long, pre-symptomatic phases (World Alzheimer Report, 2009, http://www.alz.co.uk/research/files/WorldAlzheimerReport.pdf). In the United States alone, over five million people suffer from Alzheimer’s disease (AD), at an estimated annual cost of $200 billion, and a projection for 13 million patients by 2050. The high prevalence of AD is of particular concern because of the lack of success in developing effective therapeutics: in comparison to most classes of disease – from neoplasia to cardiovascular and cerebrovascular disease to osteoporosis to diabetes to mental illness – therapeutic development for AD has been, to date, a failure. Why?…

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Prionic Loops, Anti-Prions, and Dependence Receptors in Neurodegeneration

…Neurodegeneration and programmed cell death (pcd)
Stan had discovered and coined the term prions in 1982, and when I established my own laboratory in 1989, I wanted to address two related questions: First, why do neurons degenerate in neurodegenerative diseases such as Creutzfeldt-Jakob disease and Alzheimer’s disease? Second, is the neurodegenerative process mediated by developmentally-related, physiological signaling, or is it mediated by purely pathological, non physiological processes? To address these questions, we needed a simple, rapidly iterative, genetically manipulable yet disease-relevant model, and unfortunately, no such model existed in 1989 (which made me envy the oncology researchers, who had well characterized cell culture phenotypes, readily transfectable cells, and remarkable in vitro-in vivo correlations in their model systems). Furthermore, there was resistance to developing and utilizing such a model: at neurodegenerative meetings in the early 1990s it was argued that any process that occurred rapidly in an in vitro system was unlikely to have much relevance for processes that occurred over years in vivo in chronic neurodegenerative conditions. It seemed like a rational argument at the time, but fortunately it turned out to be incorrect.…

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Direct Transcriptional Effects of Apolipoprotein E

A major unanswered question in biology and medicine is the mechanism by which the product of the apolipoprotein E ! 4 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 fromADpatients, 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 nano molar), and functions as a transcription factor. Using chromatin immunoprecipitation and high-throughput DNA sequencing, our results indicate that the ApoE4DNAbinding sites include! 1700 gene promoter regions. The genes associated with these promoters provide new insight into the mechanism by which AD risk is conferred by ApoE4, because they include genes associated with trophic support, programmed cell death, microtubule disassembly, synaptic function, aging, and insulin resistance, all processes that have been implicated in AD pathogenesis.

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Another Role for ApoE?

Key Alzheimer’s disease-related protein may be a transcriptional regulator.

The allele apolipoprotein E c4 (APOE £4) is the greatest genetic risk factor for Alzheimer’s disease (AD), but the role of the ApoE4 protein in AD has long been elusive. Turns out, ApoE4 may function as a transcription factor, according to a study published today (January 20) in the The Journal of Neuroscience, led by investigators at the Buck Institute for Aging Research and the University of California, Los Angeles (UCLA).

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Metabolic profiling distinguishes three subtypes of Alzheimer’s disease

Alzheimer’s disease represents a major healthcare problem, with over five million Americans estimated to suffer from this disease, and a recent study showing that AD has now become the third leading cause of death, trailing only cardiovascular disease and neoplasia [1]. The cause(s) of AD remain incompletely determined, and there is currently no truly effective treatment. However, accumulating data suggest important contributions from metabolic abnormalities such as insulin resistance, metabolic syndrome, chronic inflammation, hypovitaminosis D, hormonal deficiencies, and hyperhomocysteinemia, among others [2]. Despite this, most clinical evaluations of patients with cognitive decline do not include extensive metabolic or genomic evaluations. Furthermore, given Research Paper the perceived poor prognosis for AD, in patients with evidence of amyloid-β accumulation by amyloid PET imaging or, indirectly, by cerebrospinal fluid profile, there has been little incentive to perform extensive evaluations of hormonal status, nutritional status, toxicity status, metal status, gastrointestinal permeability, or other laboratory evaluations perceived by healthcare systems as “non-standard.”  However, studies such as the recent FINGER study [3] suggest that metabolic factors may play important roles in the neurodegenerative process, at least early in the pathogenetic process. Recent results from the evaluation of neural exosomes and nanosomes support the notion that metabolic abnormalities are present in patients with cognitive decline, often years prior to diagnosis of AD [4]. Therefore, it may be productive, both from the standpoint of identifying novel biomarkers and from the standpoint of identifying treatable metabolic abnormalities, to perform metabolic profiling of patients with cognitive decline and those at risk for such decline.

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Inhalational Alzheimer’s disease: An unrecognized—and treatable—epidemic

Alzheimer’s disease is now the third leading cause of death in the United States, following only cardiovascular disease and cancer [1]. There are approximately 5.2 million Americans with AD, but this estimate ignores the many young Americans destined to develop AD during their lifetimes: given the lifetime risk of approximately 15% when including all ApoE genotypes, as many as 45 million of the 318 million Americans now living may develop AD during their lifetimes if no prevention is instituted [2].

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Reversal of cognitive decline: A novel therapeutic program

Cognitive decline is a major concern of the aging population, and Alzheimer’s disease is the major cause of age-related cognitive decline, with approximately 5.4 million American patients and 30 million affected globally[1]. In the absence of effective prevention and treatment, the prospects for the future are of great concern, with 13 million Americans and 160 million globally projected for 2050, leading to potential bankruptcy of the Medicare system. Unlike several other chronic illnesses, Alzheimer’s disease prevalence is on the rise, which makes the need to develop effective prevention and treatment increasingly pressing. Recent estimates suggest that AD has become the third leading cause of death in the United States [2], behind cardiovascular disease and cancer. Furthermore, it has been pointed out recently that women are at the epicenter of the Alzheimer’s epidemic, with 65% of patients and 60% of caregivers being women [3]. Indeed, a woman’s chance of developing AD is now greater than her chance of developing breast cancer [4].

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