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Cerebrovascular Dysfunction in Amyloid Precursor Protein Transgenic Mice: Contribution of Soluble and Insoluble Amyloid-β Peptide, Partial Restoration via γ-Secretase Inhibition
Open accessAbstract
The contributing effect of cerebrovascular pathology in Alzheimer's disease (AD) has become increasingly appreciated. Recent evidence suggests that amyloid-β peptide (Aβ), the same peptide found in neuritic plaques of AD, may play a role via its vasoactive properties. Several studies have examined young Tg2576 mice expressing mutant amyloid precursor protein (APP) and having elevated levels of soluble Aβ but no cerebral amyloid angiopathy (CAA). These studies suggest but do not prove that soluble Aβ can significantly impair the cerebral circulation. Other studies examining older Tg2576 mice having extensive CAA found even greater cerebrovascular dysfunction, suggesting that CAA is likely to further impair vascular function. Herein, we examined vasodilatory responses in young and older Tg2576 mice to further assess the roles of soluble and insoluble Aβ on vessel function. We found that (1) vascular impairment was present in both young and older Tg2576 mice; (2) a strong correlation between CAA severity and vessel reactivity exists; (3) a surprisingly small amount of CAA led to marked reduction or complete loss of vessel function; 4) CAA-induced vasomotor impairment resulted from dysfunction rather than loss or disruption of vascular smooth muscle cells; and 5) acute depletion of Aβ improved vessel function in young and to a lesser degree older Tg2576 mice. These results strongly suggest that both soluble and insoluble Aβ cause cerebrovascular dysfunction, that mechanisms other than Aβ-induced alteration in vessel integrity are responsible, and that anti-Aβ therapy may have beneficial vascular effects in addition to positive effects on parenchymal amyloid.
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“Deposition of amyloid-β within microvessels is highly frequent in patients with Alzheimer’s disease dementia (Kalaria, 2016) and associated with reduced blood flow in transgenic mouse models (Han et al., 2008; Saito et al., 2017) and humans (Chung et al., 2009; Dumas et al., 2012).”
From White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer’s disease (2018) · cites this paper as Han et al., 2008
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“evidence for this possibility comes from animal models in which exogenously applied or genetically overexpressed Aβ production diminished vasodilation to pharmacological or physiological stimuli, even in the absence of vascular Aβ deposits.115,160,161”
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Metadata
- Authors
- Han, B. H., Zhou, M.-L., Abousaleh, F., Brendza, R. P., Dietrich, H. H., Koenigsknecht-Talboo, J., Cirrito, J. R., Milner, E., Holtzman, D. M., & Zipfel, G. J.
- Affiliations
- Washington University in St. Louis (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-12-10
- Volume
- 28
- Issue
- 50
- Pages
- 13542-13550
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2626633
- OpenAlex
- W2032210346
- Cited by
- 138
- References
- 63
- Citations by year
- 2026: 1 · 2025: 8 · 2024: 2 · 2023: 10 · 2022: 3 · 2021: 4 · 2020: 7 · 2019: 4 · 2018: 4 · 2017: 12 · 2016: 10 · 2015: 11 · 2014: 10 · 2013: 11 · 2012: 12
- FWCI
- 6.55
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Health Assistance Foundation
- Eli Lilly and Company
- Congress of Neurological Surgeons
- National Institutes of Health (NS057105)
- National Institute of Neurological Disorders and Stroke (R25NS090978, P30NS057105, NS057105, P01NS032636, K08NS053899, NS-032636, NS053899)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- cerebrovascular dysfunction, amyloid-beta, cerebral amyloid angiopathy, Alzheimer's disease, Tg2576 mice, amyloid precursor protein, soluble amyloid-beta, gamma-secretase inhibition, vasodilation, vascular smooth muscle cells, anti-amyloid therapy
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cerebrovascular Circulation, Mice, Transgenic, Muscle, Smooth, Vascular, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Cerebral Amyloid Angiopathy, Mice, Amyloid Precursor Protein Secretases
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