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Sökning: id:"swepub:oai:DiVA.org:uu-98584" > Targeting Early Sta...

LIBRIS Formathandbok  (Information om MARC21)
FältnamnIndikatorerMetadata
00003964nam a2200361 4500
001oai:DiVA.org:uu-98584
003SwePub
008090226s2009 | |||||||||||000 ||eng|
020 a 9789155474430q print
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-985842 URI
040 a (SwePub)uu
041 a engb eng
042 9 SwePub
072 7a vet2 swepub-contenttype
072 7a dok2 swepub-publicationtype
1001 a Lord, Anna,d 1979-u Uppsala universitet,Institutionen för folkhälso- och vårdvetenskap4 aut0 (Swepub:uu)anlor424
2451 0a Targeting Early Stages of Alzheimer’s Disease in a Transgenic Model
264 1a Uppsala :b Acta Universitatis Upsaliensis,c 2009
300 a 66 s.
338 a electronic2 rdacarrier
4900 a Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine,x 1651-6206 ;v 432
520 a The Arctic mutation causes early-onset Alzheimer’s disease (AD), and makes amyloid-β (Aβ) peptides more prone to form Aβ protofibrils. The aims of this thesis were to investigate the mechanisms of the Arctic mutation in vivo, and to use transgenic models to determine the role of early intermediates of Aβ aggregation, like protofibrils, in the pathogenesis. In addition, we aimed to evaluate protofibrils as a therapeutic target.Transgenic models with Arctic and Swedish mutations (tg-ArcSwe), and with the Swedish mutation alone (tg-Swe) were created. The Arctic mutation favored amyloidogenic processing of amyloid-β precursor protein (APP) in transgenic mice and cultured cells. The observed shift in the subcellular location and processing of APP led to increased production of intracellular Aβ in vitro, and also partly explained the early accumulation of intraneuronal Aβ in tg-ArcSwe mice. The intraneuronal Aβ in combination with enhanced levels of protofibrils appeared long before extracellular plaques emerged. Elevated protofibril levels were associated with intraneuronal Aβ and linked to spatial learning deficits in young mice, suggesting that protofibrils cause AD-related cognitive deficits. The Arctic mutation also enhanced senile plaque pathology in aged tg-ArcSwe mice, and the accelerated plaque deposition was accompanied by decreased intraneuronal Aβ. This suggests a dynamic equilibrium between the early accumulation of intraneuronal Aβ and the later senile plaque pathology.Aβ protofibrils were evaluated as a therapeutic target in tg-ArcSwe mice with passive immunization using a protofibril-selective antibody. This treatment cleared protofibrils without removing senile plaques. However, plaque formation was prevented if treatment began early, indicating that protofibrils are intermediate species of Aβ fibrillization in vivo. Targeting senile plaques with immunotherapy requires early diagnosis and intervention, whereas protofibrils can be specifically cleared from brain despite substantial AD-like deposition of insoluble Aβ. The early and persistent presence of protofibrils throughout Aβ amyloidosis makes them a promising target for future diagnostic and therapeutic strategies in AD.
653 a Geriatrics
653 a geriatrik
7001 a Nilsson, Lars,c Docentu Uppsala universitet,Geriatrik4 ths
7001 a Lannfelt, Lars,c Professoru Uppsala universitet,Geriatrik4 ths
7001 a Ekholm Pettersson, Frida,c PhDu Uppsala universitet,Geriatrik4 ths
7001 a Bayer, Thomas,c Professoru Department for Psychiatry, University of Goettingen4 opn
7102 a Uppsala universitetb Institutionen för folkhälso- och vårdvetenskap4 org
8564 u https://uu.diva-portal.org/smash/get/diva2:175102/FULLTEXT01.pdfx primaryx Raw objecty fulltext
8564 u https://uu.diva-portal.org/smash/get/diva2:175102/INSIDE01.pdfy inside
8564 u https://uu.diva-portal.org/smash/get/diva2:175102/COVER01.pdfy cover
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-98584

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