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      Alzheimer's Disease and Non-Demented High Pathology Control Nonagenarians: Comparing and Contrasting the Biochemistry of Cognitively Successful Aging

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          Abstract

          The amyloid cascade hypothesis provides an economical mechanistic explanation for Alzheimer's disease (AD) dementia and correlated neuropathology. However, some nonagenarian individuals (high pathology controls, HPC) remain cognitively intact while enduring high amyloid plaque loads for decades. If amyloid accumulation is the prime instigator of neurotoxicity and dementia, specific protective mechanisms must enable these HPC to evade cognitive decline. We evaluated the neuropathological and biochemical differences existing between non-demented (ND)-HPC and an age-matched cohort with AD dementia. The ND-HPC selected for our study were clinically assessed as ND and possessed high amyloid plaque burdens. ELISA and Western blot analyses were used to quantify a group of proteins related to APP/Aβ/tau metabolism and other neurotrophic and inflammation-related molecules that have been found to be altered in neurodegenerative disorders and are pivotal to brain homeostasis and mental health. The molecules assumed to be critical in AD dementia, such as soluble or insoluble Aβ40, Aβ42 and tau were quantified by ELISA. Interestingly, only Aβ42 demonstrated a significant increase in ND-HPC when compared to the AD group. The vascular amyloid load which was not used in the selection of cases, was on the average almost 2-fold greater in AD than the ND-HPC, suggesting that a higher degree of microvascular dysfunction and perfusion compromise was present in the demented cohort. Neurofibrillary tangles were less frequent in the frontal cortices of ND-HPC. Biochemical findings included elevated vascular endothelial growth factor, apolipoprotein E and the neuroprotective factor S100B in ND-HPC, while anti-angiogenic pigment epithelium derived factor levels were lower. The lack of clear Aβ-related pathological/biochemical demarcation between AD and ND-HPC suggests that in addition to amyloid plaques other factors, such as neurofibrillary tangle density and vascular integrity, must play important roles in cognitive failure.

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          Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis.

          Soluble oligomers are common to most amyloids and may represent the primary toxic species of amyloids, like the Abeta peptide in Alzheimer's disease (AD). Here we show that all of the soluble oligomers tested display a common conformation-dependent structure that is unique to soluble oligomers regardless of sequence. The in vitro toxicity of soluble oligomers is inhibited by oligomer-specific antibody. Soluble oligomers have a unique distribution in human AD brain that is distinct from fibrillar amyloid. These results indicate that different types of soluble amyloid oligomers have a common structure and suggest they share a common mechanism of toxicity.
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            A specific amyloid-beta protein assembly in the brain impairs memory.

            Memory function often declines with age, and is believed to deteriorate initially because of changes in synaptic function rather than loss of neurons. Some individuals then go on to develop Alzheimer's disease with neurodegeneration. Here we use Tg2576 mice, which express a human amyloid-beta precursor protein (APP) variant linked to Alzheimer's disease, to investigate the cause of memory decline in the absence of neurodegeneration or amyloid-beta protein amyloidosis. Young Tg2576 mice ( 14 months old) form abundant neuritic plaques containing amyloid-beta (refs 3-6). We found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid-beta assembly, which we term Abeta*56 (Abeta star 56). Abeta*56 purified from the brains of impaired Tg2576 mice disrupts memory when administered to young rats. We propose that Abeta*56 impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficits associated with Alzheimer's disease.
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              Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI.

              We have used restriction isotyping (restriction enzyme isoform genotyping) for rapid typing of common apolipoprotein E isoforms (E2, E3, E4). ApoE restriction isotyping used oligonucleotides to amplify apolipoprotein E gene sequences containing amino acid positions 112 and 158. The amplification products were digested with HhaI and subjected to electrophoresis on polyacrylamide gels. Each of the isoforms was distinguished by a unique combination of HhaI fragment sizes that enabled unambiguous typing of all homozygotic and heterozygotic combinations. HhaI cleaves at GCGC encoding 112arg (E4) and 158arg (E3, E4), but does not cut at GTGC encoding 112cys (E2, E3) and 158cys (E2).
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                7 November 2011
                : 6
                : 11
                : e27291
                Affiliations
                [1 ]The Longtine Center for Neurodegenerative Biochemistry, Banner Sun Health Research Institute, Sun City, Arizona, United States of America
                [2 ]Department of Microbiology, Midwestern University, Glendale, Arizona, United States of America
                [3 ]Laboratory of Neuroinflammation, Banner Sun Health Research Institute, Sun City, Arizona, United States of America
                [4 ]Department of Pathology, Oregon Health & Science University, Portland, Oregon, United States of America
                [5 ]Layton Aging and Alzheimer's Disease Center, Department of Neurology, Oregon Health and Science University, United States of America
                [6 ]Fundacion Instituto Leloir, Buenos Aires, Argentina
                [7 ]Cleo Roberts Center for Clinical Research, Banner Sun Health Research Institute, Sun City, Arizona, United States of America
                [8 ]Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, Arizona, United States of America
                National Institute on Aging Intramural Research Program, United States of America
                Author notes

                Conceived and designed the experiments: CLM TAK DGW JMH TGB AER. Performed the experiments: CLM IDD DGW JMH JCK. Analyzed the data: CLM TAK DGW JMH TGB AER. Contributed reagents/materials/analysis tools: TGB AER. Wrote the paper: CLM TAK DGW JMH RW JK EMC MNS TGB AER.

                Article
                PONE-D-11-17028
                10.1371/journal.pone.0027291
                3210154
                22087282
                32fa7b61-6033-4d50-970b-8cfae9e8ad14
                Maarouf et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 18 August 2011
                : 13 October 2011
                Page count
                Pages: 17
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Neurological System
                Biochemistry
                Neurochemistry
                Neuroscience
                Cellular Neuroscience
                Proteomics
                Protein Abundance
                Medicine
                Anatomy and Physiology
                Physiological Processes
                Aging
                Neurology
                Dementia
                Alzheimer Disease
                Neurodegenerative Diseases

                Uncategorized
                Uncategorized

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