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Biochemical stages of amyloid-β peptide aggregation and accumulation in the human brain and their association with symptomatic and pathologically preclinical Alzheimer's disease.

Abstract

Alzheimer's disease is characterized by the deposition of amyloid-β peptide in the brain. N-terminal truncation resulting in the formation of AβN3pE and phosphorylation at serine 8 have been reported to modify aggregation properties of amyloid-β. Biochemically, soluble, dispersible, membrane-associated, and insoluble, plaque-associated amyloid-β aggregates have been distinguished. Soluble and dispersible amyloid-β aggregates are both in mixture with the extracellular or intracellular fluid but dispersible aggregates can be cleared from proteins in solution by ultracentrifugation. To clarify the role of phosphorylated amyloid-β and AβN3pE in soluble, dispersible, membrane-associated, and plaque-associated amyloid-β aggregates in the pathogenesis of Alzheimer's disease we studied brains from 21 cases with symptomatic Alzheimer's disease, 33 pathologically preclinical Alzheimer's disease cases, and 20 control cases. Western blot analysis showed that soluble, dispersible, membrane-associated and plaque-associated amyloid-β aggregates in the earliest preclinical stage of Alzheimer's disease did not exhibit detectable amounts of AβN3pE and phosphorylated amyloid-β. This stage was referred to as biochemical stage 1 of amyloid-β aggregation and accumulation. In biochemical amyloid-β stage 2, AβN3pE was additionally found whereas phosphorylated amyloid-β was restricted to biochemical amyloid-β stage 3, the last stage of amyloid-β aggregation. Phosphorylated amyloid-β was seen in the dispersible, membrane-associated, and plaque-associated fraction. All cases with symptomatic Alzheimer's disease in our sample fulfilled biochemical amyloid-β stage 3 criteria, i.e. detection of phosphorylated amyloid-β. Most, but not all, cases with pathologically preclinical Alzheimer's disease had biochemical amyloid-β stages 1 or 2. Immunohistochemistry confirmed the hierarchical occurrence of amyloid-β, AβN3pE, and phosphorylated amyloid-β in amyloid plaques. Phosphorylated amyloid-β containing plaques were, thereby, seen in all symptomatic cases with Alzheimer's disease but only in a few non-demented control subjects. The biochemical amyloid-β stages correlated with the expansion of amyloid-β plaque deposition and with that of neurofibrillary tangle pathology. Taken together, we demonstrate that AβN3pE and phosphorylated amyloid-β are not only detectable in plaques, but also in soluble and dispersible amyloid-β aggregates outside of plaques. They occur in a hierarchical sequence that allows the distinction of three stages. In light of our findings, it is tempting to speculate that this hierarchical, biochemical sequence of amyloid-β aggregation and accumulation is related to disease progression and may be relevant for an increasing toxicity of amyloid-β aggregates.

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  • Authors+Show Affiliations

    ,

    1 Laboratory of Neuropathology, Institute of Pathology, Centre for Clinical Research at the University of Ulm, Ulm, Germany.

    , , , , , ,

    Source

    Brain : a journal of neurology 137:Pt 3 2014 Mar pg 887-903

    MeSH

    Adult
    Aged
    Aged, 80 and over
    Alzheimer Disease
    Amyloid beta-Peptides
    Blotting, Western
    Cerebral Cortex
    Disease Progression
    Female
    Humans
    Male
    Middle Aged
    Occipital Lobe
    Phosphorylation
    Plaque, Amyloid
    Prodromal Symptoms
    Temporal Lobe

    Pub Type(s)

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

    Language

    eng

    PubMed ID

    24519982

    Citation

    Rijal Upadhaya, Ajeet, et al. "Biochemical Stages of Amyloid-β Peptide Aggregation and Accumulation in the Human Brain and Their Association With Symptomatic and Pathologically Preclinical Alzheimer's Disease." Brain : a Journal of Neurology, vol. 137, no. Pt 3, 2014, pp. 887-903.
    Rijal Upadhaya A, Kosterin I, Kumar S, et al. Biochemical stages of amyloid-β peptide aggregation and accumulation in the human brain and their association with symptomatic and pathologically preclinical Alzheimer's disease. Brain. 2014;137(Pt 3):887-903.
    Rijal Upadhaya, A., Kosterin, I., Kumar, S., von Arnim, C. A., Yamaguchi, H., Fändrich, M., ... Thal, D. R. (2014). Biochemical stages of amyloid-β peptide aggregation and accumulation in the human brain and their association with symptomatic and pathologically preclinical Alzheimer's disease. Brain : a Journal of Neurology, 137(Pt 3), pp. 887-903. doi:10.1093/brain/awt362.
    Rijal Upadhaya A, et al. Biochemical Stages of Amyloid-β Peptide Aggregation and Accumulation in the Human Brain and Their Association With Symptomatic and Pathologically Preclinical Alzheimer's Disease. Brain. 2014;137(Pt 3):887-903. PubMed PMID: 24519982.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Biochemical stages of amyloid-β peptide aggregation and accumulation in the human brain and their association with symptomatic and pathologically preclinical Alzheimer's disease. AU - Rijal Upadhaya,Ajeet, AU - Kosterin,Irina, AU - Kumar,Sathish, AU - von Arnim,Christine A F, AU - Yamaguchi,Haruyasu, AU - Fändrich,Marcus, AU - Walter,Jochen, AU - Thal,Dietmar Rudolf, Y1 - 2014/02/10/ PY - 2014/2/13/entrez PY - 2014/2/13/pubmed PY - 2014/5/27/medline KW - N-terminal truncation KW - amyloid-β protein KW - dispersible fraction KW - phosphorylation KW - pyroglutamate formation KW - soluble fraction SP - 887 EP - 903 JF - Brain : a journal of neurology JO - Brain VL - 137 IS - Pt 3 N2 - Alzheimer's disease is characterized by the deposition of amyloid-β peptide in the brain. N-terminal truncation resulting in the formation of AβN3pE and phosphorylation at serine 8 have been reported to modify aggregation properties of amyloid-β. Biochemically, soluble, dispersible, membrane-associated, and insoluble, plaque-associated amyloid-β aggregates have been distinguished. Soluble and dispersible amyloid-β aggregates are both in mixture with the extracellular or intracellular fluid but dispersible aggregates can be cleared from proteins in solution by ultracentrifugation. To clarify the role of phosphorylated amyloid-β and AβN3pE in soluble, dispersible, membrane-associated, and plaque-associated amyloid-β aggregates in the pathogenesis of Alzheimer's disease we studied brains from 21 cases with symptomatic Alzheimer's disease, 33 pathologically preclinical Alzheimer's disease cases, and 20 control cases. Western blot analysis showed that soluble, dispersible, membrane-associated and plaque-associated amyloid-β aggregates in the earliest preclinical stage of Alzheimer's disease did not exhibit detectable amounts of AβN3pE and phosphorylated amyloid-β. This stage was referred to as biochemical stage 1 of amyloid-β aggregation and accumulation. In biochemical amyloid-β stage 2, AβN3pE was additionally found whereas phosphorylated amyloid-β was restricted to biochemical amyloid-β stage 3, the last stage of amyloid-β aggregation. Phosphorylated amyloid-β was seen in the dispersible, membrane-associated, and plaque-associated fraction. All cases with symptomatic Alzheimer's disease in our sample fulfilled biochemical amyloid-β stage 3 criteria, i.e. detection of phosphorylated amyloid-β. Most, but not all, cases with pathologically preclinical Alzheimer's disease had biochemical amyloid-β stages 1 or 2. Immunohistochemistry confirmed the hierarchical occurrence of amyloid-β, AβN3pE, and phosphorylated amyloid-β in amyloid plaques. Phosphorylated amyloid-β containing plaques were, thereby, seen in all symptomatic cases with Alzheimer's disease but only in a few non-demented control subjects. The biochemical amyloid-β stages correlated with the expansion of amyloid-β plaque deposition and with that of neurofibrillary tangle pathology. Taken together, we demonstrate that AβN3pE and phosphorylated amyloid-β are not only detectable in plaques, but also in soluble and dispersible amyloid-β aggregates outside of plaques. They occur in a hierarchical sequence that allows the distinction of three stages. In light of our findings, it is tempting to speculate that this hierarchical, biochemical sequence of amyloid-β aggregation and accumulation is related to disease progression and may be relevant for an increasing toxicity of amyloid-β aggregates. SN - 1460-2156 UR - https://www.unboundmedicine.com/medline/citation/24519982/Biochemical_stages_of_amyloid_β_peptide_aggregation_and_accumulation_in_the_human_brain_and_their_association_with_symptomatic_and_pathologically_preclinical_Alzheimer's_disease_ L2 - https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awt362 DB - PRIME DP - Unbound Medicine ER -