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      Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells

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          Abstract

          Our understanding of Alzheimer’s disease pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of the disease. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). Here we reprogrammed primary fibroblasts from two patients with familial Alzheimer’s disease, both caused by a duplication of the amyloid-β precursor protein gene 1 ( APP; termed APP Dp), two with sporadic Alzheimer’s disease (termed sAD1, sAD2) and two non-demented control individuals into iPSC lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain messenger RNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APP Dp patients and patient sAD2 exhibited significantly higher levels of the pathological markers amyloid-β(1–40), phospho-tau(Thr 231) and active glycogen synthase kinase-3β (aGSK-3β). Neurons from APP Dp and sAD2 patients also accumulated large RAB5-positive early endosomes compared to controls. Treatment of purified neurons with β-secretase inhibitors, but not γ-secretase inhibitors, caused significant reductions in phospho-Tau(Thr 231) and aGSK-3β levels. These results suggest a direct relationship between APP proteolytic processing, but not amyloid-β, in GSK-3β activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial Alzheimer’s disease samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to Alzheimer’s disease, even though it can take decades for overt disease to manifest in patients.

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          Most cited references26

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          Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease.

          We studied the accumulation of neurofibrillary tangles (NFTs) and senile plaques (SPs) in 10 Alzheimer's disease patients who had been examined during life. We counted NFTs and SPs in 13 cytoarchitectural regions representing limbic, primary sensory, and association cortices, and in subcortical neurotransmitter-specific areas. The degree of neuropathologic change was compared with the severity of dementia, as assessed by the Blessed Dementia Scale and duration of illness. We found that (1) the severity of dementia was positively related to the number of NFTs in neocortex, but not to the degree of SP deposition; (2) NFTs accumulate in a consistent pattern reflecting hierarchic vulnerability of individual cytoarchitectural fields; (3) NFTs appeared in the entorhinal cortex, CA1/subiculum field of the hippocampal formation, and the amygdala early in the disease process; and (4) the degree of SP deposition was also related to a hierarchic vulnerability of certain brain areas to accumulate SPs, but the pattern of SP distribution was different from that of NFT.
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            Tau-mediated neurodegeneration in Alzheimer's disease and related disorders.

            Advances in our understanding of the mechanisms of tau-mediated neurodegeneration in Alzheimer's disease (AD) and related tauopathies, which are characterized by prominent CNS accumulations of fibrillar tau inclusions, are rapidly moving this previously underexplored disease pathway to centre stage for disease-modifying drug discovery efforts. However, controversies abound concerning whether or not the deleterious effects of tau pathologies result from toxic gains-of-function by pathological tau or from critical losses of normal tau function in the disease state. This Review summarizes the most recent advances in our knowledge of the mechanisms of tau-mediated neurodegeneration to forge an integrated concept of those tau-linked disease processes that drive the onset and progression of AD and related tauopathies.
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              Induced pluripotent stem cells from a spinal muscular atrophy patient.

              Spinal muscular atrophy is one of the most common inherited forms of neurological disease leading to infant mortality. Patients have selective loss of lower motor neurons resulting in muscle weakness, paralysis and often death. Although patient fibroblasts have been used extensively to study spinal muscular atrophy, motor neurons have a unique anatomy and physiology which may underlie their vulnerability to the disease process. Here we report the generation of induced pluripotent stem cells from skin fibroblast samples taken from a child with spinal muscular atrophy. These cells expanded robustly in culture, maintained the disease genotype and generated motor neurons that showed selective deficits compared to those derived from the child's unaffected mother. This is the first study to show that human induced pluripotent stem cells can be used to model the specific pathology seen in a genetically inherited disease. As such, it represents a promising resource to study disease mechanisms, screen new drug compounds and develop new therapies.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                4 February 2012
                25 January 2012
                09 August 2012
                : 482
                : 7384
                : 216-220
                Affiliations
                [1 ]Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, USA
                [2 ]Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, California 92093, USA
                [3 ]Department of Neurosciences, University of California, San Diego, La Jolla, California, USA
                [4 ]The Salk Institute for Biological Studies, La Jolla, California 92037, USA
                [5 ]Department of Anesthesiology, University of California, San Diego, La Jolla, California 92093, USA
                [6 ]Department of Anesthesiology, Maastricht University Medical Center, Maastricht 6202 AZ, Netherlands
                [7 ]Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA
                [8 ]Department of Reproductive Medicine, University of California, San Diego, La Jolla, California 92093, USA
                [9 ]BD Biosciences, La Jolla, California 92037, USA
                [10 ]Institute of Neurobiology, Slovak Academy of Sciences, Kosice SK-04001, Slovakia
                [11 ]Department of Clinical Medicine, Neurology and Clinical Research Center, University of Oulu, Oulu FIN-90015, Finland
                Author notes
                Correspondence and requests for materials should be addressed to L.S.B.G. ( lgoldstein@ 123456ucsd.edu )
                Article
                nihpa352073
                10.1038/nature10821
                3338985
                22278060
                f1b19939-8d5e-41f8-9336-d07456d54f21
                ©2012 Macmillan Publishers Limited. All rights reserved

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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