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Altered amyloid-β s...
Altered amyloid-β structure markedly reduces gliosis in the brain of mice harboring the Uppsala APP deletion
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- Pagnon de la Vega, María (author)
- Uppsala universitet,Molekylär geriatrik
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- Syvänen, Stina (author)
- Uppsala universitet,Molekylär geriatrik
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- Giedraitis, Vilmantas (author)
- Uppsala universitet,Klinisk geriatrik
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- Hooley, Monique (author)
- Univ Edinburgh, UK Dementia Res Inst, Edinburgh Med Sch, Edinburgh, Scotland.;Univ Edinburgh, Ctr Discovery Brain Sci, Edinburgh, Scotland.
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- Konstantinidis, Evangelos, 1990- (author)
- Uppsala universitet,Molekylär geriatrik
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- Meier, Silvio R. (author)
- Uppsala universitet,Geriatrik
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- Rokka, Johanna (author)
- Uppsala universitet,Geriatrik
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- Eriksson, Jonas (author)
- Uppsala universitet,Preparativ läkemedelskemi,Uppsala Univ Hosp, PET Ctr, Uppsala, Sweden
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- Aguilar, Ximena (author)
- Uppsala universitet,Molekylär geriatrik
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- Spires-Jones, Tara L. (author)
- Univ Edinburgh, UK Dementia Res Inst, Edinburgh Med Sch, Edinburgh, Scotland.;Univ Edinburgh, Ctr Discovery Brain Sci, Edinburgh, Scotland.
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- Lannfelt, Lars (author)
- Uppsala universitet,Molekylär geriatrik,BioArctic AB, Stockholm, Sweden
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- Nilsson, Lars N. G. (author)
- Oslo Univ Hosp, Dept Pharmacol, Oslo, Norway.;Oslo Univ Hosp, Oslo, Norway.
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- Erlandsson, Anna (author)
- Uppsala universitet,Molekylär geriatrik
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- Hultqvist, Greta, 1980- (author)
- Uppsala universitet,Institutionen för farmaci
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- Ingelsson, Martin (author)
- Uppsala universitet,Molekylär geriatrik,Univ Hlth Network, Krembil Brain Inst, Toronto, ON, Canada; Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Dept Med & Lab Med, Toronto, ON, Canada; Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Dept Pathobiol, Toronto, ON, Canada
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- Sehlin, Dag, 1976- (author)
- Uppsala universitet,Molekylär geriatrik
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(creator_code:org_t)
- BioMed Central (BMC), 2024
- 2024
- English.
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In: Acta neuropathologica communications. - : BioMed Central (BMC). - 2051-5960. ; 12:1
- Related links:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- Deposition of amyloid beta (Aβ) into plaques is a major hallmark of Alzheimer’s disease (AD). Different amyloid precursor protein (APP) mutations cause early-onset AD by altering the production or aggregation properties of Aβ. We recently identified the Uppsala APP mutation (APPUpp), which causes Aβ pathology by a triple mechanism: increased β-secretase and altered α-secretase APP cleavage, leading to increased formation of a unique Aβ conformer that rapidly aggregates and deposits in the brain. The aim of this study was to further explore the effects of APPUpp in a transgenic mouse model (tg-UppSwe), expressing human APP with the APPUpp mutation together with the APPSwe mutation. Aβ pathology was studied in tg-UppSwe brains at different ages, using ELISA and immunohistochemistry. In vivo PET imaging with three different PET radioligands was conducted in aged tg-UppSwe mice and two other mouse models; tg-ArcSwe and tg-Swe. Finally, glial responses to Aβ pathology were studied in cell culture models and mouse brain tissue, using ELISA and immunohistochemistry. Tg-UppSwe mice displayed increased β-secretase cleavage and suppressed α-secretase cleavage, resulting in AβUpp42 dominated diffuse plaque pathology appearing from the age of 5–6 months. The γ-secretase cleavage was not affected. Contrary to tg-ArcSwe and tg-Swe mice, tg-UppSwe mice were [11C]PiB-PET negative. Antibody-based PET with the 3D6 ligand visualized Aβ pathology in all models, whereas the Aβ protofibril selective mAb158 ligand did not give any signals in tg-UppSwe mice. Moreover, unlike the other two models, tg-UppSwe mice displayed a very faint glial response to the Aβ pathology. The tg-UppSwe mouse model thus recapitulates several pathological features of the Uppsala APP mutation carriers. The presumed unique structural features of AβUpp42 aggregates were found to affect their interaction with anti-Aβ antibodies and profoundly modify the Aβ-mediated glial response, which may be important aspects to consider for further development of AD therapies.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
Keyword
- Alzheimer's disease (AD)
- Amyloid precursor protein (APP)
- Amyloid-beta (A beta)
- PET imaging
- Microglia
- Astrocytes
- Immunotherapy
Publication and Content Type
- ref (subject category)
- art (subject category)
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Pagnon de la Veg ...
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Syvänen, Stina
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Giedraitis, Vilm ...
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Hooley, Monique
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Konstantinidis, ...
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Meier, Silvio R.
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show more...
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Rokka, Johanna
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Eriksson, Jonas
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Aguilar, Ximena
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Spires-Jones, Ta ...
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Lannfelt, Lars
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Nilsson, Lars N. ...
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Erlandsson, Anna
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Hultqvist, Greta ...
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Ingelsson, Marti ...
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Sehlin, Dag, 197 ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Neurosciences
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Neurology
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Acta neuropathol ...
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Uppsala University