Article

Amyloid-β protofibril levels correlate with spatial learning in Arctic Alzheimer's disease transgenic mice

Department of Public Health and Caring Sciences/Molecular Geriatrics, Uppsala University, Sweden.
FEBS Journal (Impact Factor: 4). 03/2009; 276(4):995-1006. DOI: 10.1111/j.1742-4658.2008.06836.x
Source: PubMed

ABSTRACT

Oligomeric assemblies of amyloid-beta (Abeta) are suggested to be central in the pathogenesis of Alzheimer's disease because levels of soluble Abeta correlate much better with the extent of cognitive dysfunctions than do senile plaque counts. Moreover, such Abeta species have been shown to be neurotoxic, to interfere with learned behavior and to inhibit the maintenance of hippocampal long-term potentiation. The tg-ArcSwe model (i.e. transgenic mice with the Arctic and Swedish Alzheimer mutations) expresses elevated levels of Abeta protofibrils in the brain, making tg-ArcSwe a highly suitable model for investigating the pathogenic role of these Abeta assemblies. In the present study, we estimated Abeta protofibril levels in the brain and cerebrospinal fluid of tg-ArcSwe mice, and also assessed their role with respect to cognitive functions. Protofibril levels, specifically measured with a sandwich ELISA, were found to be elevated in young tg-ArcSwe mice compared to several transgenic models lacking the Arctic mutation. In aged tg-ArcSwe mice with considerable plaque deposition, Abeta protofibrils were approximately 50% higher than in younger mice, whereas levels of total Abeta were exponentially increased. Young tg-ArcSwe mice showed deficits in spatial learning, and individual performances in the Morris water maze were correlated inversely with levels of Abeta protofibrils, but not with total Abeta levels. We conclude that Abeta protofibrils accumulate in an age-dependent manner in tg-ArcSwe mice, although to a far lesser extent than total Abeta. Our findings suggest that increased levels of Abeta protofibrils could result in spatial learning impairment.

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    • "Tg-ArcSwe model has an early onset of senile plaque formation (4–6 months) and 152 increased intraneuronal Ab aggregation (1 month) prior to the extracellular Ab 153 deposition (Lord et al., 2006, 2009, 2011) The mice were age-matched and all 154 experimental procedures were performed following institutionally approved 155 protocols in accordance with strict international regulations for the care and use 156 of laboratory animals. The experiment was approved by the section for comparative 157 medicine at the University of Oslo and the Norwegian Animal Research Authority/ 158 Biological Research Ethics Committee, and complied with national laws, "
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    ABSTRACT: Alzheimer's disease (AD) is a disease of major public health significance, whose pathogenesis is strongly linked to the presence of fibrillar aggregates of amyloid-beta (Aβ) in the aging human brain. We exploited the transgenic (Tg)-ArcSwe mouse model for human AD to explore whether oxidative stress and the capacity to repair oxidative DNA damage via base excision repair (BER) are related to Aβ pathology in AD. Tg-ArcSwe mice express variants of Aβ, accumulating senile plaques at 4-6 months of age, and develop AD-like neuropathology as adult animals. The relative mRNA levels of genes encoding BER enzymes, including 8-oxoguanine glycosylase (OGG1), AP endonuclease 1 (APE1), polymerase β (Polβ) and poly (ADP-ribose) polymerase 1 (PARP1), were quantified in various brain regions of 6 weeks, 4 months and 12 months old mice. The results show that OGG1 transcriptional expression was higher, and APE1 expression lower, in 4 months old Tg-ArcSwe than in wildtype (wt) mice. Furthermore, Polβ transcriptional expression was significantly lower in transgenic 12 months old mice than in wt. Transcriptional profiling also showed that BER repair capacity vary during the lifespan in Tg-ArcSwe and wt mice. The BER expression pattern in Tg-ArcSwe mice thus reflects responses to oxidative stress in vulnerable brain structures.
    Full-text · Article · Oct 2013 · Mechanisms of ageing and development
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    • "Antibody Epitope/Target Manufacturer N-terminal Aβ-antibodies mAb 82E1 Neoepitope Aβ1-5 IBL, Hamburg, Germany mAb 6E10 Aβ5-10 Covance, Berkeley, CA, USA Mid-domain Aβ-antibodies mAb 6F/3D Aβ8-17 Novocastra, Newcastle, U.K. mAb 4G8 Aβ17-24 Covance C-terminal Aβ-antibodies rpAb 40 Aβx-40, neoepitope Biosource/Invitrogen, Camarillo CA, USA rpAb 42 Aβx-42, neoepitope Biosource/Invitrogen Special Aβ-antibodies mAb 27 Aβ20-24 with Arc-mutation p.E22G Lord et al. 2009 [19] mAb 2-48 Aβ3pE Synaptic Systems, Göttingen, Germany rpAb 11pE Aβ11pE Synaptic Systems Antibodies to cellular alterations mAb AT8 Hyperphosphorylated tau Innogenetics, Zwijndrecht, Belgium mAb GFAP Glial fibrillary acidic protein Dako, Glostrup, Denmark mAb HLA-DP, DQ, DR Microglial cells Dako rpAb Iba1 Microglial cells Wako, Osaka, Japan rpAbα1-antitrypsin Lysosomes Dako rpAb cathepsin D Lysosomes Dako (production discontinued) "
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    ABSTRACT: The Arctic mutation (p.E693G/p.E22G)fs within the β-amyloid (Aβ) region of the β-amyloid precursor protein gene causes an autosomal dominant disease with clinical picture of typical Alzheimer's disease. Here we report the special character of Arctic AD neuropathology in four deceased patients. Aβ deposition in the brains was wide-spread (Thal phase 5) and profuse. Virtually all parenchymal deposits were composed of non-fibrillar, Congo red negative Aβ aggregates. Congo red only stained angiopathic vessels. Mass spectrometric analyses showed that Aβ deposits contained variably truncated and modified wild type and mutated Aβ species. In three of four Arctic AD brains, most cerebral cortical plaques appeared targetoid with centres containing C-terminally (beyond aa 40) and variably N-terminally truncated Aβ surrounded by coronas immunopositive for Aβx-42. In the fourth patient plaque centres contained almost no Aβ making the plaques ring-shaped. The architectural pattern of plaques also varied between different anatomic regions. Tau pathology corresponded to Braak stage VI, and appeared mainly as delicate neuropil threads (NT) enriched within Aβ plaques. Dystrophic neurites were scarce, while neurofibrillary tangles were relatively common. Neuronal perikarya within the Aβ plaques appeared relatively intact. In Arctic AD brain differentially truncated abundant Aβ is deposited in plaques of variable numbers and shapes in different regions of the brain (including exceptional targetoid plaques in neocortex). The extracellular non-fibrillar Aβ does not seem to cause overt damage to adjacent neurons or to induce formation of neurofibrillary tangles, supporting the view that intracellular Aβ oligomers are more neurotoxic than extracellular Aβ deposits. However, the enrichment of NTs within plaques suggests some degree of intra-plaque axonal damage including accumulation of hp-tau, which may impair axoplasmic transport, and thereby contribute to synaptic loss. Finally, similarly as the cotton wool plaques in AD resulting from exon 9 deletion in the presenilin-1 gene, the Arctic plaques induced only modest glial and inflammatory tissue reaction.
    Full-text · Article · Sep 2013
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    • "Antibody Epitope/Target Manufacturer N-terminal Aβ-antibodies mAb 82E1 Neoepitope Aβ1-5 IBL, Hamburg, Germany mAb 6E10 Aβ5-10 Covance, Berkeley, CA, USA Mid-domain Aβ-antibodies mAb 6F/3D Aβ8-17 Novocastra, Newcastle, U.K. mAb 4G8 Aβ17-24 Covance C-terminal Aβ-antibodies rpAb 40 Aβx-40, neoepitope Biosource/Invitrogen, Camarillo CA, USA rpAb 42 Aβx-42, neoepitope Biosource/Invitrogen Special Aβ-antibodies mAb 27 Aβ20-24 with Arc-mutation p.E22G Lord et al. 2009 [19] mAb 2-48 Aβ3pE Synaptic Systems, Göttingen, Germany rpAb 11pE Aβ11pE Synaptic Systems Antibodies to cellular alterations mAb AT8 Hyperphosphorylated tau Innogenetics, Zwijndrecht, Belgium mAb GFAP Glial fibrillary acidic protein Dako, Glostrup, Denmark mAb HLA-DP, DQ, DR Microglial cells Dako rpAb Iba1 Microglial cells Wako, Osaka, Japan rpAbα1-antitrypsin Lysosomes Dako rpAb cathepsin D Lysosomes Dako (production discontinued) "
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: The Arctic mutation (p.E693G/p.E22G)fs within the β-amyloid (Aβ) region of the β-amyloid precursor protein gene causes an autosomal dominant disease with clinical picture of typical Alzheimer's disease. Here we report the special character of Arctic AD neuropathology in four deceased patients. RESULTS: Aβ deposition in the brains was wide-spread (Thal phase 5) and profuse. Virtually all parenchymal deposits were composed of non-fibrillar, Congo red negative Aβ aggregates. Congo red only stained angiopathic vessels. Mass spectrometric analyses showed that Aβ deposits contained variably truncated and modified wild type and mutated Aβ species. In three of four Arctic AD brains, most cerebral cortical plaques appeared targetoid with centres containing C-terminally (beyond aa 40) and variably N-terminally truncated Aβ surrounded by coronas immunopositive for Aβx-42. In the fourth patient plaque centres contained almost no Aβ making the plaques ring-shaped. The architectural pattern of plaques also varied between different anatomic regions. Tau pathology corresponded to Braak stage VI, and appeared mainly as delicate neuropil threads (NT) enriched within Aβ plaques. Dystrophic neurites were scarce, while neurofibrillary tangles were relatively common. Neuronal perikarya within the Aβ plaques appeared relatively intact. CONCLUSIONS: In Arctic AD brain differentially truncated abundant Aβ is deposited in plaques of variable numbers and shapes in different regions of the brain (including exceptional targetoid plaques in neocortex). The extracellular non-fibrillar Aβ does not seem to cause overt damage to adjacent neurons or to induce formation of neurofibrillary tangles, supporting the view that intracellular Aβ oligomers are more neurotoxic than extracellular Aβ deposits. However, the enrichment of NTs within plaques suggests some degree of intra-plaque axonal damage including accumulation of hp-tau, which may impair axoplasmic transport, and thereby contribute to synaptic loss. Finally, similarly as the cotton wool plaques in AD resulting from exon 9 deletion in the presenilin-1 gene, the Arctic plaques induced only modest glial and inflammatory tissue reaction.
    Full-text · Article · Sep 2013
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