Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Modeling Amyloid-β Pathology in Alzheimer’s Disease Using the Arctic Mutation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences. (Geriatrik)
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. , p. 67
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 560
Keywords [en]
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: urn:nbn:se:uu:diva-120919ISBN: 978-91-554-7810-0 (print)OAI: oai:DiVA.org:uu-120919DiVA, id: diva2:311248
Public defence
2010-06-04, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Note
(Faculty of medicine)Available from: 2010-05-11 Created: 2010-03-17 Last updated: 2010-05-18
List of papers
1.
The record could not be found. The reason may be that the record is no longer available or you may have typed in a wrong id in the address field.
2. Genetic and pharmacological evidence of intraneuronal Abeta accumulation in APP transgenic mice
Open this publication in new window or tab >>Genetic and pharmacological evidence of intraneuronal Abeta accumulation in APP transgenic mice
2009 (English)In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 583, no 18, p. 3021-3026Article in journal (Refereed) Published
Abstract [en]

Intraneuronal punctate immunostaining in Alzheimer's disease brain and amyloid-beta precursor protein (APP) transgenic mice has been suggested to represent Abeta, but this is somewhat controversial. Here we show that both biochemical Abeta levels and intraneuronal immunostaining are reduced in APP transgenic mice when gamma-secretase is inhibited. Moreover, BACE-1 deficient APP transgenic mice show neither Abeta production nor intraneuronal immunostaining. Our findings suggest that the punctate immunostaining with APP antibodies is due to Abeta that has accumulated inside neurons. Similar type of intraneuronal Abeta accumulation, which precedes senile plaque formation, may link Abeta to tauopathy and neurodegeneration in Alzheimer's disease pathogenesis.

Keywords
Amyloid precursor protein secretases, amyloid beta protein, bace1 protein, mouse, immunohistochemistry, intracellular space, mice, transgenic
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-114175 (URN)10.1016/j.febslet.2009.08.009 (DOI)000271284200009 ()19683527 (PubMedID)
Available from: 2010-02-11 Created: 2010-02-11 Last updated: 2017-12-12Bibliographically approved
3. Biochemical and morphological analyses of Aβ deposits in postmortem brain of Arctic APP mutation carriers
Open this publication in new window or tab >>Biochemical and morphological analyses of Aβ deposits in postmortem brain of Arctic APP mutation carriers
Show others...
(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.

Keywords
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:nbn:se:uu:diva-123029 (URN)
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
4. Arctic Aβ selectively increases diffuse deposition of wild type Aβ in APP transgenic mice with the Swedish mutation
Open this publication in new window or tab >>Arctic Aβ selectively increases diffuse deposition of wild type Aβ in APP transgenic mice with the Swedish mutation
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Studies of familial Alzheimer´s disease (AD) suggest that misfolding and aggregation of amyloid-β (Aβ) peptides initiate the pathogenesis, which causes dementia. The Arctic amyloid precursor protein (APP) mutation results in AD, and Arctic Aβ is more prone to form Aβ protofibrils. Here we show that the number of diffuse Aβ deposits, but not amyloid plaques, is increased if tg-ArcSwe mice synthesizing a low level of Arctic Aβ are crossed with plaque-depositing tg-Swe mice. The diffuse deposits in bitransgenic mice, which contain mainly wild type Aβ42, accumulate in regions both with and without transgene expression. The selective increase of a single type of parenchymal Aβ deposit suggest that different pathways of Aβ aggregation lead to the formation of diffuse and compact Aβ deposits in the brain. The raise in diffuse deposits is most likely due to direct physical interactions between Arctic and wild type Aβ42, and not to altered APP processing in young bitransgenic mice. A mixture of Arctic and wild type Aβ42 facilitates the formation of prefibrillar and fibrillar Aβ assemblies, but inhibits the further elongation of Aβ fibrils in vitro. Our findings might have implications to the pathogenesis of patients who are heterozygous for the Arctic mutation. It also further illustrates how Aβ neuropathology can be manipulated in vivo in a manner reminiscent to prion disorders.    

Keywords
Alzheimer‘s disease, amyloid-β protein, senile plaque, Arctic mutation, Swedish mutation, immunohistochemistry
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Research subject
Geriatrics
Identifiers
urn:nbn:se:uu:diva-123035 (URN)
Projects
Philipson, Ola. Modeling amyloid-β pathology in Alzheimer´s disease pathology using the Arctic mutation
Available from: 2010-04-22 Created: 2010-04-22 Last updated: 2010-05-11

Open Access in DiVA

fulltext(2787 kB)642 downloads
File information
File name FULLTEXT01.pdfFile size 2787 kBChecksum SHA-512
092206a7f987a936bf2d45a3a897768351c17c332b24981e6bbac51bed24f9f32bb0b9ec751ab0e9ba5e98e06711939db3881ef87675f5a8f24d7b561c9c4dd0
Type fulltextMimetype application/pdf
Buy this publication >>

By organisation
Department of Public Health and Caring Sciences
Public Health, Global Health, Social Medicine and Epidemiology

Search outside of DiVA

GoogleGoogle Scholar
Total: 642 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 1462 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf