Vascular and parenchymal amyloid pathology in an Alzheimer disease knock-in mouse model: interplay with cerebral blood flow
Open accessAbstract
BACKGROUND: Accumulation and deposition of β-amyloid peptides (Aβ) in the brain is a central event in the pathogenesis of Alzheimer's disease (AD). Besides the parenchymal pathology, Aβ is known to undergo active transport across the blood-brain barrier and cerebral amyloid angiopathy (CAA) is a prominent feature in the majority of AD. Although impaired cerebral blood flow (CBF) has been implicated in faulty Aβ transport and clearance, and cerebral hypoperfusion can exist in the pre-clinical phase of Alzheimer's disease (AD), it is still unclear whether it is one of the causal factors for AD pathogenesis, or an early consequence of a multi-factor condition that would lead to AD at late stage. To study the potential interaction between faulty CBF and amyloid accumulation in clinical-relevant situation, we generated a new amyloid precursor protein (APP) knock-in allele that expresses humanized Aβ and a Dutch mutation in addition to Swedish/London mutations and compared this line with an equivalent knock-in line but in the absence of the Dutch mutation, both crossed onto the PS1M146V knock-in background. RESULTS: Introduction of the Dutch mutation results in robust CAA and parenchymal Aβ pathology, age-dependent reduction of spatial learning and memory deficits, and CBF reduction as detected by fMRI. Direct manipulation of CBF by transverse aortic constriction surgery on the left common carotid artery caused differential changes in CBF in the anterior and middle region of the cortex, where it is reduced on the left side and increased on the right side. However these perturbations in CBF resulted in the same effect: both significantly exacerbate CAA and amyloid pathology. CONCLUSIONS: Our study reveals a direct and positive link between vascular and parenchymal Aβ; both can be modulated by CBF. The new APP knock-in mouse model recapitulates many symptoms of AD including progressive vascular and parenchymal Aβ pathology and behavioral deficits in the absence of APP overexpression.
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To date, Aβ pathologies and cognitive deficits were observed only when two or three familial AD mutations were combined.
“To date, however, Aβ pathologies and cognitive deficits were observed only when two or three familial AD mutations were combined [33–35].”
From Amyloid-β plaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer’s disease (2019) · cites this paper as [35]
The Materials and methods (Animals; page unavailable) describe mice carrying Dutch, Swedish and London APP mutations crossed with PS1 M146V mice—four mutations in total. The Discussion (page unavailable) reports amyloid pathology and spatial learning and memory deficits in these mice. This supports the association with combined mutations, but not the claim that the pathologies and deficits were observed only with two or three. (LLM, conf=0.87)
Experimental — accuracy not yet measuredKnock-in of the Swedish, London and Dutch mutations only results in the development of plaques if bred onto a PS1M146V knock-in background.
“For example, knock-in of the Swedish, London and Dutch mutations only results in the development of plaques if bred onto a PS1M146V knock-in background [93].”
From Alzheimer's disease: experimental models and reality (2017) · cites this paper as [93]
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- Authors
- Li, H., Guo, Q., Inoue, T., Polito, V. A., Tabuchi, K., Hammer, R. E., Pautler, R. G., Taffet, G. E., & Zheng, H.
- Affiliations
- Baylor College of Medicine (US)
- Shinshu University (JP)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Zheng, Hui
- ORCID
- Venue
- Molecular Neurodegeneration
- Published
- 2014-08-09
- Volume
- 9
- Issue
- 1
- Pages
- 28-28
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC4132280
- OpenAlex
- W2167043901
- Cited by
- 86
- References
- 55
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 8 · 2023: 3 · 2022: 9 · 2021: 13 · 2020: 5 · 2019: 8 · 2018: 3 · 2017: 10 · 2016: 6 · 2015: 11
- FWCI
- 6.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- BrightFocus Foundation (A2013370F)
- National Institutes of Health (AG020670)
- Intellectual and Developmental Disabilities Research Center (HD024064)
- National Institute on Aging (AG032051, AG020670, R01AG032051, R01AG020670)
- National Institute of Neurological Disorders and Stroke (R01NS076117, NS076117)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 024064, U54HD083092, P30HD024064)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, cerebral amyloid angiopathy, cerebral blood flow, amyloid precursor protein, transverse aortic constriction, cerebral hypoperfusion, blood-brain barrier, spatial learning and memory deficits
- MeSH terms
- Alzheimer Disease, Animals, Behavior, Animal, Brain, Cerebrovascular Circulation, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Fluorescent Antibody Technique, Humans, Immunohistochemistry, Magnetic Resonance Imaging, Amyloid beta-Peptides, Cerebral Amyloid Angiopathy, Mice, Gene Knock-In Techniques
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