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Therapeutic and functional studies in animal models of Alzheimer's disease
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. (Molecular Geriatrics)
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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 protofibril-selective antibody was found to be a promising treatment for AD. The IntelliCage system was proven to be useful for functional evaluation of AβPP mice. Exon 10 in tau was shown to affect sensorimotor functions and Aβ pathology in bitransgenic mice by mechanisms that deserve further investigation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. , 73 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1003
Keyword [en]
Alzheimer's disease, Amyloid-beta, Immunotherapy, IntelliCage, Microtubule, Tau, Alternative splicing
National Category
Neurosciences Microbiology in the medical area
Research subject
Neuroscience; Medical Cell Biology; Medical Biochemistry
URN: urn:nbn:se:uu:diva-223135ISBN: 978-91-554-8961-8OAI: diva2:713716
Public defence
2014-06-12, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Available from: 2014-05-22 Created: 2014-04-16 Last updated: 2014-09-18Bibliographically approved
List of papers
1. An amyloid-beta protofibril-selective antibody prevents amyloid formation in a mouse model of Alzheimer's disease
Open this publication in new window or tab >>An amyloid-beta protofibril-selective antibody prevents amyloid formation in a mouse model of Alzheimer's disease
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2009 (English)In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 36, no 3, 425-434 p.Article in journal (Refereed) Published
Abstract [en]

Human genetics link Alzheimer's disease pathogenesis to excessive accumulation of amyloid-beta (Abeta) in brain, but the symptoms do not correlate with senile plaque burden. Since soluble Abeta aggregates can cause synaptic dysfunctions and memory deficits, these species could contribute to neuronal dysfunction and dementia. Here we explored selective targeting of large soluble aggregates, Abeta protofibrils, as a new immunotherapeutic strategy. The highly protofibril-selective monoclonal antibody mAb158 inhibited in vitro fibril formation and protected cells from Abeta protofibril-induced toxicity. When the mAb158 antibody was administered for 4 months to plaque-bearing transgenic mice with both the Arctic and Swedish mutations (tg-ArcSwe), Abeta protofibril levels were lowered while measures of insoluble Abeta were unaffected. In contrast, when treatment began before the appearance of senile plaques, amyloid deposition was prevented and Abeta protofibril levels diminished. Therapeutic intervention with mAb158 was however not proven functionally beneficial, since place learning depended neither on treatment nor transgenicity. Our findings suggest that Abeta protofibrils can be selectively cleared with immunotherapy in an animal model that display highly insoluble Abeta deposits, similar to those of Alzheimer's disease brain.

Alzheimer's disease, Immunotherapy, Monoclonal antibody, Soluble amyloid-beta, Intraneuronal, Transgenic mice
National Category
Medical and Health Sciences
urn:nbn:se:uu:diva-123188 (URN)10.1016/j.nbd.2009.08.007 (DOI)000271689400003 ()19703562 (PubMedID)
Available from: 2010-04-26 Created: 2010-04-26 Last updated: 2015-02-23Bibliographically approved
2. Impaired behavior of female tg-ArcSwe APP mice in the IntelliCage: A longitudinal study
Open this publication in new window or tab >>Impaired behavior of female tg-ArcSwe APP mice in the IntelliCage: A longitudinal study
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2010 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 215, no 1, 83-94 p.Article in journal (Refereed) Published
Abstract [en]

Transgenic animals expressing mutant human amyloid precursor protein (APP) are used as models for Alzheimer disease (AD). Ideally, behavioral tests improve the predictive validity of studies on animals by mirroring the functional impact of AD-like neuropathology. Learning and memory studies in APP transgenic models have been difficult to replicate. Standardization of procedures, automatization or improved protocol design can improve reproducibility. Here the IntelliCage, an automated system, was used for behavioral testing of APP female transgenic mice with both the Arctic and Swedish mutations, the tg-ArcSwe model. Protocols covering exploration, operant learning, place learning and extinction of place preference as well as passive avoidance tests were used for longitudinal characterization of behavior. Differences in exploratory activity were significant at four months of age, when plaque-free tg-ArcSwe mice visited less frequently the IntelliCage corners and initially performed fewer visits with licks compared to non-tg animals, inside the new environment. Fourteen months old tg-ArcSwe mice required a longer time to re-habituate to the IntelliCages than non-tg mice. At both ages tg-ArcSwe mice perseverated in place preference extinction test. Fourteen months old tg-ArcSwe mice were impaired in hippocampus-dependent spatial passive avoidance learning. This deficit was found to inversely correlate to calbindin-D28k immunoreactivity in the polymorphic layer of the dentate gyrus. Reduced water intake and body weight were observed in 4 months old tg-ArcSwe animals. The body weight difference increased with age. Thus behavioral and metabolic changes in the tg-ArcSwe APP model were detected using the IntelliCage, a system which provides the opportunity for standardized automated longitudinal behavioral phenotyping.

Alzheimer's disease, Transgenic mice, IntelliCage, Passive avoidance learning, Calbindin-D28k, Amyloid-beta, Arctic mutation, Behavior
National Category
Medical and Health Sciences
urn:nbn:se:uu:diva-134890 (URN)10.1016/j.bbr.2010.06.034 (DOI)000282076500011 ()20615433 (PubMedID)
Available from: 2010-12-02 Created: 2010-12-02 Last updated: 2014-06-30Bibliographically approved
3. Lack of exon 10 in the murine tau gene results in mild sensorimotor defects with aging
Open this publication in new window or tab >>Lack of exon 10 in the murine tau gene results in mild sensorimotor defects with aging
2013 (English)In: BMC neuroscience (Online), ISSN 1471-2202, Vol. 14, 148- p.Article in journal (Refereed) Published
Abstract [en]

Background: Complex species-specific, developmental-and tissue-dependent mechanisms regulate alternative splicing of tau, thereby diversifying tau protein synthesis. The functional role of alternative splicing of tau e. g. exon 10 has never been examined in vivo, although genetic studies suggest that it is important to neurodegenerative disease. Results: Gene-targeting was used to delete exon 10 in murine tau on both alleles (E10-/-) to study its functional role. Moreover, mice devoid of exon 10 (E10+/-) on one allele were generated to investigate the effects of 1: 1 balanced expression of 4R-/3R-tau protein, since equal amounts of 4R-/3R-tau protein are synthesized in human brain. Middle-aged E10-/-mice displayed sensorimotor disturbances in the rotarod when compared to age-matched E10+/- and wild-type mice, and their muscular grip strength was less than that of E10+/-mice. The performance of E10+/-mice and wild-type mice (E10+/+) was similar in sensorimotor tests. Cognitive abilities or anxiety-like behaviours did not depend on exon 10 in tau, and neither pathological inclusions nor gene-dependent morphological abnormalities were found. Conclusion: Ablation of exon 10 in the murine tau gene alters alternative splicing and tau protein synthesis which results in mild sensorimotor phenotypes with aging. Presumably related microtubule-stabilizing genes rescue other functions.

Alzheimer's disease, Tau, Knockout mice, Alternative splicing, Microtubule
National Category
Medical and Health Sciences
urn:nbn:se:uu:diva-217677 (URN)10.1186/1471-2202-14-148 (DOI)000329428100001 ()
Available from: 2014-02-04 Created: 2014-02-04 Last updated: 2014-06-30Bibliographically approved
4. Effects of humanized exon 10 splicing in murine tau on pathological phenotypes in tg-ArcSwe mice
Open this publication in new window or tab >>Effects of humanized exon 10 splicing in murine tau on pathological phenotypes in tg-ArcSwe mice
(English)Manuscript (preprint) (Other academic)
Alzheimer's disease, Alternative splicing, amyloid deposition, bitransgenic mice, Microtubule, Tau
National Category
Neurosciences Cell and Molecular Biology
urn:nbn:se:uu:diva-222767 (URN)
Available from: 2014-04-16 Created: 2014-04-14 Last updated: 2014-06-30

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