Therapeutic and functional studies in animal models of Alzheimer's disease
Senile plaques (Aβ) and neurofibrillary tangles (tau) are pathological hallmarks of Alzheimer’s disease (AD). If and how the formation of these deposits are mechanistically linked remains mainly unknown. In recent years, the focus has shifted from insoluble protein deposits to soluble aggregates of...
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ftuppsalauniv:oai:DiVA.org:uu-223135 2023-05-15T15:16:41+02:00 Therapeutic and functional studies in animal models of Alzheimer's disease Gumucio, Astrid 2014 application/pdf http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-223135 eng eng Uppsala universitet, Geriatrik Uppsala Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 1003 http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-223135 urn:isbn:978-91-554-8961-8 info:eu-repo/semantics/openAccess Alzheimer's disease Amyloid-beta Immunotherapy IntelliCage Microtubule Tau Alternative splicing Neurosciences Neurovetenskaper Microbiology in the medical area Mikrobiologi inom det medicinska området Doctoral thesis, comprehensive summary info:eu-repo/semantics/doctoralThesis text 2014 ftuppsalauniv 2023-02-23T21:46:18Z Senile plaques (Aβ) and neurofibrillary tangles (tau) are pathological hallmarks of Alzheimer’s disease (AD). If and how the formation of these deposits are mechanistically linked remains mainly unknown. In recent years, the focus has shifted from insoluble protein deposits to soluble aggregates of Aβ and tau. Protofibrils are large soluble Aβ oligomers which were linked to AD by the discovery of the Arctic AβPP mutation. Treatment of young tg-ArcSwe mice with an Aβ protofibril-selective antibody, mAb158, cleared protofibrils, prevented amyloid plaque deposition and protected cultured cells from protofibril-mediated toxicity. This suggests that Aβ protofibrils are necessary for the formation of Aβ deposits. Functional assessment of tg-ArcSwe mice in IntelliCage demonstrated hippocampal-dependent behavioral deficits such as memory/learning impairments, hyperactivity and perseverance behavior. Learning impairments did not correlate to Aβ-measures but to calbindin, which might be a good marker for Aβ-mediated neuronal dysfunction. Splicing of exon 10 in the tau gene differs between human and mouse brain. Exon 10 is part of the microtubule-binding domains which helps to maintain microtubule stability and axonal transport, functions vital to neuronal viability. Axonal transport dysfunction has been proposed as a common pathway of Aβ and tau pathogenesis in AD. Generation of a novel tau mouse model with absence of exon 10 led to age-dependent sensorimotor impairments which may relate to dysfunctions in cerebellum. No tau pathology was evident suggesting that a trigger of tau fibrillization e.g. a human Aβ or tau aggregate is needed. Generation of AβPPxE10 bitransgenic mice with no exon 10 showed lower Aβ plaque burden. Possibly changes in microtubule function lead to altered intracellular AβPP transport and Aβ production. Initiation of tau pathology in AβPPxE10 mice might require a certain type of Aβ-aggregates which is not produced or exist at too low concentration in transgenic mouse brain. In summary, the Aβ ... Doctoral or Postdoctoral Thesis Arctic Uppsala University: Publications (DiVA) Arctic Perseverance ENVELOPE(162.200,162.200,-76.800,-76.800) |
institution |
Open Polar |
collection |
Uppsala University: Publications (DiVA) |
op_collection_id |
ftuppsalauniv |
language |
English |
topic |
Alzheimer's disease Amyloid-beta Immunotherapy IntelliCage Microtubule Tau Alternative splicing Neurosciences Neurovetenskaper Microbiology in the medical area Mikrobiologi inom det medicinska området |
spellingShingle |
Alzheimer's disease Amyloid-beta Immunotherapy IntelliCage Microtubule Tau Alternative splicing Neurosciences Neurovetenskaper Microbiology in the medical area Mikrobiologi inom det medicinska området Gumucio, Astrid Therapeutic and functional studies in animal models of Alzheimer's disease |
topic_facet |
Alzheimer's disease Amyloid-beta Immunotherapy IntelliCage Microtubule Tau Alternative splicing Neurosciences Neurovetenskaper Microbiology in the medical area Mikrobiologi inom det medicinska området |
description |
Senile plaques (Aβ) and neurofibrillary tangles (tau) are pathological hallmarks of Alzheimer’s disease (AD). If and how the formation of these deposits are mechanistically linked remains mainly unknown. In recent years, the focus has shifted from insoluble protein deposits to soluble aggregates of Aβ and tau. Protofibrils are large soluble Aβ oligomers which were linked to AD by the discovery of the Arctic AβPP mutation. Treatment of young tg-ArcSwe mice with an Aβ protofibril-selective antibody, mAb158, cleared protofibrils, prevented amyloid plaque deposition and protected cultured cells from protofibril-mediated toxicity. This suggests that Aβ protofibrils are necessary for the formation of Aβ deposits. Functional assessment of tg-ArcSwe mice in IntelliCage demonstrated hippocampal-dependent behavioral deficits such as memory/learning impairments, hyperactivity and perseverance behavior. Learning impairments did not correlate to Aβ-measures but to calbindin, which might be a good marker for Aβ-mediated neuronal dysfunction. Splicing of exon 10 in the tau gene differs between human and mouse brain. Exon 10 is part of the microtubule-binding domains which helps to maintain microtubule stability and axonal transport, functions vital to neuronal viability. Axonal transport dysfunction has been proposed as a common pathway of Aβ and tau pathogenesis in AD. Generation of a novel tau mouse model with absence of exon 10 led to age-dependent sensorimotor impairments which may relate to dysfunctions in cerebellum. No tau pathology was evident suggesting that a trigger of tau fibrillization e.g. a human Aβ or tau aggregate is needed. Generation of AβPPxE10 bitransgenic mice with no exon 10 showed lower Aβ plaque burden. Possibly changes in microtubule function lead to altered intracellular AβPP transport and Aβ production. Initiation of tau pathology in AβPPxE10 mice might require a certain type of Aβ-aggregates which is not produced or exist at too low concentration in transgenic mouse brain. In summary, the Aβ ... |
format |
Doctoral or Postdoctoral Thesis |
author |
Gumucio, Astrid |
author_facet |
Gumucio, Astrid |
author_sort |
Gumucio, Astrid |
title |
Therapeutic and functional studies in animal models of Alzheimer's disease |
title_short |
Therapeutic and functional studies in animal models of Alzheimer's disease |
title_full |
Therapeutic and functional studies in animal models of Alzheimer's disease |
title_fullStr |
Therapeutic and functional studies in animal models of Alzheimer's disease |
title_full_unstemmed |
Therapeutic and functional studies in animal models of Alzheimer's disease |
title_sort |
therapeutic and functional studies in animal models of alzheimer's disease |
publisher |
Uppsala universitet, Geriatrik |
publishDate |
2014 |
url |
http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-223135 |
long_lat |
ENVELOPE(162.200,162.200,-76.800,-76.800) |
geographic |
Arctic Perseverance |
geographic_facet |
Arctic Perseverance |
genre |
Arctic |
genre_facet |
Arctic |
op_relation |
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 1003 http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-223135 urn:isbn:978-91-554-8961-8 |
op_rights |
info:eu-repo/semantics/openAccess |
_version_ |
1766346988370001920 |