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Biochemical and morphological analyses of Aβ deposits in postmortem brain of Arctic APP mutation carriers
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences. (Geriatrik)
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

The clinical symptoms associated with the Arctic (E693G) mutation in the amyloid-β precursor protein (APP) are those of typical Alzheimer’s disease (AD), beginning with insidious loss of recent memories. However, an unusual neuropathology of ring-like amyloid-β (Aβ) plaques is identified in postmortem brain. Here, the neuropathology of subjects carrying the Arctic mutation was compared to that of sporadic AD. Different types of Aβ-deposits were examined with light, confocal and electron microscopy, and their composition was analyzed with biochemical techniques. Parenchymal deposits of the Arctic mutant brain were homogenous in structure, lacked an amyloid core and were immunostained differentially by antibodies recognizing C- or N-terminal epitopes of Aβ. Superficially, Arctic Aβ plaques bore considerable resemblance to cotton wool plaques (CWP), namely their large size, the presence of healthy neuronal nuclei and the absence of marked neuritic dystrophy within the plaques, and the sparsity of astro- or microgliosis in the surrounding tissue. Both parenchymal deposits and cerebral amyloid angiopathy of Arctic mutant brain contained a mixture of Arctic and wild-type Aβ. While Aβ peptides in parenchymal plaques were often N-terminally truncated, a substantial amount of full-length Aβ1-40 was deposited in the vessel walls as cerebral amyloid angiopathy (CAA). Thus, the absence of amyloid cores in parenchymal plaques of Arctic mutant brain was likely due to the scarcity of full-length Aβ species, although other mechanisms could also be involved. Our findings are discussed in relation to the clinical features of patients carrying the Arctic mutation and neuropathological observations made with other intra-Aβ mutations in human and transgenic mouse brain.

Keyword [en]
Alzheimer‘s disease, amyloid-β protein, senile plaques, Arctic mutation, Swedish mutation, immunohistochemistry, microscopy, immunoelectron microscopy, mass spectrometry
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Research subject
Geriatrics
Identifiers
URN: urn:nbn:se:uu:diva-123029OAI: oai:DiVA.org:uu-123029DiVA: diva2:311658
Projects
Philipson, Ola. Modeling amyloid-β pathology in Alzheimer´s disease using the Arctic mutation
Available from: 2010-04-22 Created: 2010-04-22 Last updated: 2010-05-11
In thesis
1. Modeling Amyloid-β Pathology in Alzheimer’s Disease Using the Arctic Mutation
Open this publication in new window or tab >>Modeling Amyloid-β Pathology in Alzheimer’s Disease Using the Arctic Mutation
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The Arctic mutation in the Amyloid-β (Aβ) domain of the Amyloid-β precursor protein (APP) causes Alzheimer’s disease (AD) and confers unique biochemical characteristics to Aβ peptides. The aims of this thesis were to evaluate a transgenic model with the Arctic mutation, and to use it to gain new insights into the mechanisms of early (pre-plaque) and late-stage Aβ pathogenesis in AD. The Arctic mutation made Aβ more prone to aggregate, to accumulate in intracellular compartments and to form extracellular plaques when the models tg-ArcSwe and tg-Swe were compared. By inhibiting APP processing genetically or pharmacologically, the intraneuronal granular immunoreactivity with antibodies binding the Aβ domain was shown to largely represent Aβ, and not APP or APP-fragments. At two months of age, the intracellularly accumulated Aβ decreased rapidly, likely because it was still accessible to intracellular clearance. Extracellular Aβ deposits emerged at 5-6 months of age and the amyloid fibril structure was more compact than in tg-Swe. Moreover, Aβ deposits in tg-ArcSwe were more resistant to chemical extraction than those of established models carrying the Swedish APP mutation only, e.g. tg-Swe mice. The stability of deposits better reflects the biochemistry of senile plaques in AD. Thus, the tg-ArcSwe model may better predict the outcome of clinical trials, particularly therapies designed to enhance clearance of Aβ aggregates and deposits. Postmortem brain of Arctic mutation carriers contained extensive parenchymal plaque pathology. Differential immunostaining patterns with C- and N-terminal Aβ antibodies revealed a subset of plaques that were unique to the brains of Arctic mutation carriers. Aβ deposits in the cerebral vessel walls were congophilic and mainly composed of full-length Aβ. In contrast, N-terminally truncated Aβ was more prominent in the parenchymal plaques, all of which essentially lacked amyloid cores. A heterogeneous assembly of mutant and wild-type Aβ was shown to favor the formation of diffuse deposits in bitransgenic mice, and such mechanisms may at least partly explain observations of plaques lacking amyloid cores in postmortem Arctic mutant brain. In the bitransgenic mice, a low level of Arctic Aβ was sufficient to facilitate aggregation of wild-type Aβ. This observation, but also our findings of differences in amyloid fibril structure in tg-ArcSwe and tg-Swe, further highlights similarities between AD and prion disorders in which PrPsc refolds PrPc and facilitates fibril formation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 67 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 560
Keyword
Alzheimer’s disease, Amyloid, Amyloid-β, intraneuronal, transgenic mice, immunohistochemistry, ELISA
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Research subject
Geriatrics
Identifiers
urn:nbn:se:uu:diva-120919 (URN)978-91-554-7810-0 (ISBN)
Public defence
2010-06-04, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
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Supervisors
Note
(Faculty of medicine)Available from: 2010-05-11 Created: 2010-03-17 Last updated: 2010-05-18

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