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Sporadic Alzheimer's disease begins as episodes of brain ischemia and ischemically dysregulated Alzheimer's disease genes.

Abstract

The study of sporadic Alzheimer's disease etiology, now more than ever, needs an infusion of new concepts. Despite ongoing interest in Alzheimer's disease, the basis of this entity is not yet clear. At present, the best-established and accepted "culprit" in Alzheimer's disease pathology by most scientists is the amyloid, as the main molecular factor responsible for neurodegeneration in this disease. Abnormal upregulation of amyloid production or a disturbed clearance mechanism may lead to pathological accumulation of amyloid in brain according to the "amyloid hypothesis." We will critically review these observations and highlight inconsistencies between the predictions of the "amyloid hypothesis" and the published data. There is still controversy over the role of amyloid in the pathological process. A question arises whether amyloid is responsible for the neurodegeneration or if it accumulates because of the neurodegeneration. Recent evidence suggests that the pathophysiology and neuropathology of Alzheimer's disease comprises more than amyloid accumulation, tau protein pathology and finally brain atrophy with dementia. Nowadays, a handful of researchers share a newly emerged view that the ischemic episodes of brain best describe the pathogenic cascade, which eventually leads to neuronal loss, especially in hippocampus, with amyloid accumulation, tau protein pathology and irreversible dementia of Alzheimer type. The most persuasive evidences come from investigations of ischemically damaged brains of patients and from experimental ischemic brain studies that mimic Alzheimer-type dementia. This review attempts to depict what we know and do not know about the triggering factor of the Alzheimer's disease, focusing on the possibility that the initial pathological trigger involves ischemic episodes and ischemia-induced gene dysregulation. The resulting brain ischemia dysregulates additionally expression of amyloid precursor protein and amyloid-processing enzyme genes that, in addition, ultimately compromise brain functions, leading over time to the complex alterations that characterize advanced sporadic Alzheimer's disease. The identification of the genes involved in Alzheimer's disease induced by ischemia will enable to further define the events leading to sporadic Alzheimer's disease-related abnormalities. Additionally, knowledge gained from the above investigations should facilitate the elaboration of the effective treatment and/or prevention of Alzheimer's disease.

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  • Authors+Show Affiliations

    ,

    Laboratory of Ischemic and Neurodegenerative Brain Research, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Str., 02-106, Warsaw, Poland, pluta@cmdik.pan.pl.

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    Source

    Molecular neurobiology 48:3 2013 Dec pg 500-15

    MeSH

    Alzheimer Disease
    Amyloid beta-Peptides
    Animals
    Blood-Brain Barrier
    Brain Ischemia
    Dementia
    Gene Expression Regulation
    Humans

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't
    Review

    Language

    eng

    PubMed ID

    23519520

    Citation

    Pluta, Ryszard, et al. "Sporadic Alzheimer's Disease Begins as Episodes of Brain Ischemia and Ischemically Dysregulated Alzheimer's Disease Genes." Molecular Neurobiology, vol. 48, no. 3, 2013, pp. 500-15.
    Pluta R, Jabłoński M, Ułamek-Kozioł M, et al. Sporadic Alzheimer's disease begins as episodes of brain ischemia and ischemically dysregulated Alzheimer's disease genes. Mol Neurobiol. 2013;48(3):500-15.
    Pluta, R., Jabłoński, M., Ułamek-Kozioł, M., Kocki, J., Brzozowska, J., Januszewski, S., ... Czuczwar, S. J. (2013). Sporadic Alzheimer's disease begins as episodes of brain ischemia and ischemically dysregulated Alzheimer's disease genes. Molecular Neurobiology, 48(3), pp. 500-15. doi:10.1007/s12035-013-8439-1.
    Pluta R, et al. Sporadic Alzheimer's Disease Begins as Episodes of Brain Ischemia and Ischemically Dysregulated Alzheimer's Disease Genes. Mol Neurobiol. 2013;48(3):500-15. PubMed PMID: 23519520.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Sporadic Alzheimer's disease begins as episodes of brain ischemia and ischemically dysregulated Alzheimer's disease genes. AU - Pluta,Ryszard, AU - Jabłoński,Mirosław, AU - Ułamek-Kozioł,Marzena, AU - Kocki,Janusz, AU - Brzozowska,Judyta, AU - Januszewski,Sławomir, AU - Furmaga-Jabłońska,Wanda, AU - Bogucka-Kocka,Anna, AU - Maciejewski,Ryszard, AU - Czuczwar,Stanisław J, Y1 - 2013/03/22/ PY - 2013/02/02/received PY - 2013/03/05/accepted PY - 2013/3/23/entrez PY - 2013/3/23/pubmed PY - 2014/6/19/medline SP - 500 EP - 15 JF - Molecular neurobiology JO - Mol. Neurobiol. VL - 48 IS - 3 N2 - The study of sporadic Alzheimer's disease etiology, now more than ever, needs an infusion of new concepts. Despite ongoing interest in Alzheimer's disease, the basis of this entity is not yet clear. At present, the best-established and accepted "culprit" in Alzheimer's disease pathology by most scientists is the amyloid, as the main molecular factor responsible for neurodegeneration in this disease. Abnormal upregulation of amyloid production or a disturbed clearance mechanism may lead to pathological accumulation of amyloid in brain according to the "amyloid hypothesis." We will critically review these observations and highlight inconsistencies between the predictions of the "amyloid hypothesis" and the published data. There is still controversy over the role of amyloid in the pathological process. A question arises whether amyloid is responsible for the neurodegeneration or if it accumulates because of the neurodegeneration. Recent evidence suggests that the pathophysiology and neuropathology of Alzheimer's disease comprises more than amyloid accumulation, tau protein pathology and finally brain atrophy with dementia. Nowadays, a handful of researchers share a newly emerged view that the ischemic episodes of brain best describe the pathogenic cascade, which eventually leads to neuronal loss, especially in hippocampus, with amyloid accumulation, tau protein pathology and irreversible dementia of Alzheimer type. The most persuasive evidences come from investigations of ischemically damaged brains of patients and from experimental ischemic brain studies that mimic Alzheimer-type dementia. This review attempts to depict what we know and do not know about the triggering factor of the Alzheimer's disease, focusing on the possibility that the initial pathological trigger involves ischemic episodes and ischemia-induced gene dysregulation. The resulting brain ischemia dysregulates additionally expression of amyloid precursor protein and amyloid-processing enzyme genes that, in addition, ultimately compromise brain functions, leading over time to the complex alterations that characterize advanced sporadic Alzheimer's disease. The identification of the genes involved in Alzheimer's disease induced by ischemia will enable to further define the events leading to sporadic Alzheimer's disease-related abnormalities. Additionally, knowledge gained from the above investigations should facilitate the elaboration of the effective treatment and/or prevention of Alzheimer's disease. SN - 1559-1182 UR - https://www.unboundmedicine.com/medline/citation/23519520/Sporadic_Alzheimer's_disease_begins_as_episodes_of_brain_ischemia_and_ischemically_dysregulated_Alzheimer's_disease_genes_ L2 - https://dx.doi.org/10.1007/s12035-013-8439-1 DB - PRIME DP - Unbound Medicine ER -