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1.
Brain ; 137(Pt 3): 887-903, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24519982

ABSTRACT

Alzheimer's disease is characterized by the deposition of amyloid-ß peptide in the brain. N-terminal truncation resulting in the formation of AßN3pE and phosphorylation at serine 8 have been reported to modify aggregation properties of amyloid-ß. Biochemically, soluble, dispersible, membrane-associated, and insoluble, plaque-associated amyloid-ß aggregates have been distinguished. Soluble and dispersible amyloid-ß 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-ß and AßN3pE in soluble, dispersible, membrane-associated, and plaque-associated amyloid-ß 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-ß aggregates in the earliest preclinical stage of Alzheimer's disease did not exhibit detectable amounts of AßN3pE and phosphorylated amyloid-ß. This stage was referred to as biochemical stage 1 of amyloid-ß aggregation and accumulation. In biochemical amyloid-ß stage 2, AßN3pE was additionally found whereas phosphorylated amyloid-ß was restricted to biochemical amyloid-ß stage 3, the last stage of amyloid-ß aggregation. Phosphorylated amyloid-ß was seen in the dispersible, membrane-associated, and plaque-associated fraction. All cases with symptomatic Alzheimer's disease in our sample fulfilled biochemical amyloid-ß stage 3 criteria, i.e. detection of phosphorylated amyloid-ß. Most, but not all, cases with pathologically preclinical Alzheimer's disease had biochemical amyloid-ß stages 1 or 2. Immunohistochemistry confirmed the hierarchical occurrence of amyloid-ß, AßN3pE, and phosphorylated amyloid-ß in amyloid plaques. Phosphorylated amyloid-ß 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-ß stages correlated with the expansion of amyloid-ß plaque deposition and with that of neurofibrillary tangle pathology. Taken together, we demonstrate that AßN3pE and phosphorylated amyloid-ß are not only detectable in plaques, but also in soluble and dispersible amyloid-ß 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-ß aggregation and accumulation is related to disease progression and may be relevant for an increasing toxicity of amyloid-ß aggregates.


Subject(s)
Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Cerebral Cortex/metabolism , Plaque, Amyloid/metabolism , Adult , Aged , Aged, 80 and over , Alzheimer Disease/classification , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/toxicity , Blotting, Western , Cerebral Cortex/chemistry , Cerebral Cortex/pathology , Disease Progression , Female , Humans , Male , Middle Aged , Occipital Lobe/chemistry , Occipital Lobe/metabolism , Occipital Lobe/pathology , Phosphorylation/physiology , Plaque, Amyloid/chemistry , Plaque, Amyloid/pathology , Prodromal Symptoms , Temporal Lobe/chemistry , Temporal Lobe/metabolism , Temporal Lobe/pathology
2.
Acta Neuropathol Commun ; 1: 77, 2013 Nov 18.
Article in English | MEDLINE | ID: mdl-24252227

ABSTRACT

BACKGROUND: The deposition of the amyloid ß-peptide (Aß) in the brain is one of the hallmarks of Alzheimer's disease (AD). It is not yet clear whether Aß always leads to similar changes or whether it induces different features of neurodegeneration in relation to its intra- and/or extracellular localization or to its intracellular trafficking routes. To address this question, we have analyzed two transgenic mouse models: APP48 and APP23 mice. The APP48 mouse expresses Aß1-42 with a signal sequence in neurons. These animals produce intracellular Aß independent of amyloid precursor protein (APP) but do not develop extracellular Aß plaques. The APP23 mouse overexpresses human APP with the Swedish mutation (KM670/671NL) in neurons and produces APP-derived extracellular Aß plaques and intracellular Aß aggregates. RESULTS: Tracing of commissural neurons in layer III of the frontocentral cortex with the DiI tracer revealed no morphological signs of dendritic degeneration in APP48 mice compared to littermate controls. In contrast, the dendritic tree of highly ramified commissural frontocentral neurons was altered in 15-month-old APP23 mice. The density of asymmetric synapses in the frontocentral cortex was reduced in 3- and 15-month-old APP23 but not in 3- and 18-month-old APP48 mice. Frontocentral neurons of 18-month-old APP48 mice showed an increased proportion of altered mitochondria in the soma compared to wild type and APP23 mice. Aß was often seen in the membrane of neuronal mitochondria in APP48 mice at the ultrastructural level. CONCLUSIONS: These results indicate that APP-independent intracellular Aß accumulation in APP48 mice is not associated with dendritic and neuritic degeneration but with mitochondrial alterations whereas APP-derived extra- and intracellular Aß pathology in APP23 mice is linked to dendrite degeneration and synapse loss independent of obvious mitochondrial alterations. Thus, Aß aggregates in APP23 and APP48 mice induce neurodegeneration presumably by different mechanisms and APP-related production of Aß may, thereby, play a role for the degeneration of neurites and synapses.


Subject(s)
Amyloid beta-Peptides/genetics , Amyloid beta-Protein Precursor/genetics , Brain/pathology , Disease Models, Animal , Mice, Transgenic , Neurodegenerative Diseases/pathology , Peptide Fragments/genetics , Aging/pathology , Aging/physiology , Alzheimer Disease , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Animals , Brain/physiopathology , Female , Male , Mice, Inbred C57BL , Mitochondria/pathology , Mitochondria/physiology , Mutation , Neurites/pathology , Neurites/physiology , Neurodegenerative Diseases/physiopathology , Neurons/pathology , Neurons/physiology , Peptide Fragments/metabolism , Synapses/pathology , Synapses/physiology
3.
Neurobiol Aging ; 33(11): 2641-60, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22305478

ABSTRACT

Soluble amyloid ß-protein (Aß) aggregates have been identified in the Alzheimer's disease (AD) brain. Dispersed Aß aggregates in the brain parenchyma are different from soluble, membrane-associated and plaque-associated solid aggregates. They are in mixture with the extra- or intracellular fluid but can be separated from soluble proteins by ultracentrifugation. To clarify the role of dispersible Aß aggregates for neurodegeneration we analyzed 2 different amyloid precursor protein (APP)-transgenic mouse models. APP23 mice overexpress human mutant APP with the Swedish mutation. APP51/16 mice express high levels of human wild type APP. Both mice develop Aß-plaques. Dendritic degeneration, neuron loss, and loss of asymmetric synapses were seen in APP23 but not in APP51/16 mice. The soluble and dispersible fractions not separated from one another were received as supernatant after centrifugation of native forebrain homogenates at 14,000 × g. Subsequent ultracentrifugation separated the soluble, i.e., the supernatant, from the dispersible fraction, i.e., the resuspended pellet. The major biochemical difference between APP23 and APP51/16 mice was that APP23 mice exhibited higher levels of dispersible Aß oligomers, protofibrils and fibrils precipitated with oligomer (A11) and protofibril/fibril (B10AP) specific antibodies than APP51/16 mice. These differences, rather than soluble Aß and Aß plaque pathology were associated with dendritic degeneration, neuron, and synapse loss in APP23 mice in comparison with APP51/16 mice. Immunoprecipitation of dispersible Aß oligomers, protofibrils, and fibrils revealed that they were associated with APP C-terminal fragments (APP-CTFs). These results indicate that dispersible Aß oligomers, protofibrils, and fibrils represent an important pool of Aß aggregates in the brain that critically interact with membrane-associated APP C-terminal fragments. The concentration of dispersible Aß aggregates, thereby, presumably determines its toxicity.


Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Protein Precursor/metabolism , Neurons/metabolism , Plaque, Amyloid/metabolism , Protein Multimerization , Synapses/pathology , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Amyloid beta-Protein Precursor/genetics , Animals , Brain/metabolism , Brain/pathology , Disease Models, Animal , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutation/genetics , Neurons/pathology , Plaque, Amyloid/pathology , Synapses/metabolism
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