The Evolution of Aβ Peptide Burden in the APP23 Transgenic Mice: Implications for Aβ Deposition in Alzheimer Disease
Open accessAbstract
BACKGROUND: High levels of A beta in the cerebral cortex distinguish demented Alzheimer's disease (AD) from nondemented elderly individuals, suggesting that decreased amyloid-beta (A beta) peptide clearance from the brain is a key precipitating factor in AD. MATERIALS AND METHODS: The levels of A beta in brain and plasma as well as apolipoprotein E (ApoE) in brain were investigated by enzyme-linked immunosorbent assay (ELISA) and Western blotting at various times during the life span of the APP23 transgenic (Tg) and control mice. Histochemistry and immunocytochemistry were used to assess the morphologic characteristics of the brain parenchymal and cerebrovascular amyloid deposits and the intracellular amyloid precursor protein (APP) deposits in the APP23 Tg mice. RESULTS: No significant differences were found in the plasma levels of A beta between the APP23 Tg and control mice from 2-20 months of age. In contrast, soluble A beta levels in the brain were continually elevated, increasing 4-fold at 2 months and 33-fold in the APP23 Tg mice at 20 months of age when compared to the control mice. Soluble A beta42 was about 60% higher than A beta40. In the APP23 Tg mice, insoluble A beta40 remained at basal levels in the brain until 9 months and then rose to 680 microg/g cortex by 20 months. Insoluble A beta40 was negligible in non-Tg mice at all ages. Insoluble A beta42 in APP23 Tg mice rose to 60 microg/g cortex at 20 months, representing 24 times the control A beta42 levels. Elevated levels of ApoE in the brain were observed in the APP23 Tg mice at 2 months of age, becoming substantially higher by 20 months. ApoE colocalized with A beta in the plaques. Beta-amyloid precursor protein (betaAPP) deposits were detected within the neuronal cytoplasm from 4 months of age onward. Amyloid angiopathy in the APP23 Tg mice increased markedly with age, being by far more severe than in the Tg2576 mice. CONCLUSIONS: We suggest that the APP23 Tg mouse may develop an earlier blockage in A beta clearance than the Tg2576 mice, resulting in a more severe accumulation of A beta in the perivascular drainage pathways and in the brain. Both Tg mice reflect decreased A beta elimination and as models for the amyloid cascade they are useful to study AD pathophysiology and therapy.
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At 12 months of age, APP23 mice have substantial Aβ plaque deposition.
“at 12 months substantial plaque deposition has been demonstrated (Kuo et al., 2001).”
From Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis (2011) · cites this paper as Kuo et al., 2001
The 80% reduction of insoluble Aβ is too extensive to be caused by prevention of Aβ deposition alone.
“Moreover, the reduction of insoluble A by 80% found in the present study seems to be too extensive to be caused by prevention of A deposition alone, based on previously reported age-dependent changes of insoluble A levels and disease progression in APP23 mice (Kuo et al., 2001).”
From Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis (2011) · cites this paper as Kuo et al., 2001
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- Authors
- Kuo, Y.-M., Beach, T. G., Sue, L. I., Scott, S., Layne, K. J., Kokjohn, T. A., Kalback, W. M., Luehrs, D. C., Vishnivetskaya, T. A., Abramowski, D., Sturchler-Pierrat, C., Staufenbiel, M., Weller, R. O., & Roher, A. E.
- Affiliations
- Banner Sun Health Research Institute (US)
- Midwestern University (US)
- Novartis (Switzerland) (CH)
- Southampton General Hospital (GB)
- Corresponding author
- Roher, Alex E.
- Venue
- Molecular Medicine
- Published
- 2001-09
- Volume
- 7
- Issue
- 9
- Pages
- 609-618
- ISSN
- 1076-1551 (ISSN-L)
- 1528-3658
- PMC
- PMC1950067
- OpenAlex
- W1493435885
- Cited by
- 90
- References
- 3
- Citations by year
- 2024: 3 · 2023: 4 · 2022: 1 · 2021: 5 · 2020: 4 · 2019: 4 · 2018: 5 · 2017: 1 · 2016: 3 · 2015: 2 · 2014: 4 · 2013: 4 · 2012: 6
- FWCI
- 2.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (AG-17490, P01AG017490)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- APP23 transgenic mice, Alzheimer's disease, amyloid-beta clearance, apolipoprotein E, amyloid plaques, amyloid angiopathy, Tg2576 mice, cerebral cortex, plasma amyloid-beta, transgenic mouse model
- MeSH terms
- Aging, Alzheimer Disease, Animals, Apolipoproteins E, Brain, Disease Models, Animal, Female, Humans, Male, Mice, Transgenic, Peptide Fragments, Time Factors, Amyloid beta-Peptides, Mice
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