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Cited by 225Alzheimer's disease research and treatmentsBarrier Structure and Function StudiesIntracerebral and Subarachnoid Hemorrhage Research

Vascular β-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAβ mice

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Merlini, Mario, Meyer, Eric P., Ulmann-Schuler, Alexandra, Nitsch, Roger M.·2011·Acta Neuropathologica
DOI 10.1007/s00401-011-0834-yPMC PMC3168476
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Abstract

Cerebrovascular lesions related to congophilic amyloid angiopathy (CAA) often accompany deposition of β-amyloid (Aβ) in Alzheimer's disease (AD), leading to disturbed cerebral blood flow and cognitive dysfunction, posing the question how cerebrovascular pathology contributes to the pathology of AD. To address this question, we characterised the morphology, biochemistry and functionality of brain blood vessels in transgenic arctic β-amyloid (arcAβ) mice expressing human amyloid precursor protein (APP) with both the familial AD-causing Swedish and Arctic mutations; these mice are characterised by strong CAA pathology. Mice were analysed at early, mid and late-stage pathology. Expression of the glucose transporter GLUT1 at the blood-brain barrier (BBB) was significantly decreased and paralleled by impaired in vivo blood-to-brain glucose transport and reduced cerebral lactate release during neuronal activation from mid-stage pathology onwards. Reductions in astrocytic GLUT1 and lactate transporters, as well as retraction of astrocyte endfeet and swelling consistent with neurovascular uncoupling, preceded wide-spread β-amyloid plaque pathology. We show that CAA at later disease stages is accompanied by severe morphological alterations of brain blood vessels including stenoses, BBB leakages and the loss of vascular smooth muscle cells (SMCs). Together, our data establish that cerebrovascular and astrocytic pathology are paralleled by impaired cerebral metabolism in arcAβ mice, and that astrocyte alterations occur already at premature stages of pathology, suggesting that astrocyte dysfunction can contribute to early behavioural and cognitive impairments seen in these mice.

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  • Aβ plaque deposition and impaired cognitive function begin at 6 months, with vascular Aβ appearing between 9 and 15 months.

    “Aβ plaque deposition and impaired cognitive function begins at 6 months (Knobloch et al., 2007b), with vascular Aβ appearing between 9 and 15 months (Merlini et al., 2011).”

    From Disrupted structural connectivity in ArcAβ mouse model of Aβ amyloidosis (2020) · cites this paper as Merlini et al., 2011

    The citation to Merlini et al. is attached to the claim that vascular Aβ appears between 9 and 15 months, not to the preceding claim about plaques and cognition. The Results (Fig. 4) report vascular Aβ deposits already at the early stage, which the Methods define as 6 months old. The deposits were few at that age, but they had appeared before 9 months. (LLM, conf=0.88)

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  • VAβ is detrimental to the function of cerebrovascular circulation through compromising blood-brain-barrier integrity, effecting hemodynamic dysfunction, and facilitating occurrence of spontaneous hemorrhages.

    “VAβ is detrimental to the function of cerebrovascular circulation through compromising blood–brain-barrier integrity [49], effecting hemodynamic dysfunction [29, 50], and facilitating occurrence of spontaneous hemorrhages [25, 26, 36].”

    From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [49]

  • The ArcAβ mice show reduced synaptic plasticity and amyloid pathology affecting both the brain parenchyma and vasculature by 6 months of age.

    “The mice show reduced synaptic plasticity (Knobloch et al., 2007a), and amyloid pathology affecting both the brain parenchyma and vasculature by 6 months of age (Knobloch et al., 2007b;Merlini et al., 2011).”

    From Early Alterations in Functional Connectivity and White Matter Structure in a Transgenic Mouse Model of Cerebral Amyloidosis (2014) · cites this paper as Merlini et al., 2011

  • The ArcAβ model displays vascular pathology at a young age, leading in old animals to cerebral microbleeds, impaired vascular reactivity, and vascular remodeling.

    “The ArcA␤ model displays vascular pathology at a young age (Merlini et al., 2011) leading in old animals to cerebral microbleeds (Klohs et al., 2011), impaired vascular reactivity (Princz-Kranz et al., 2010), and vascular remodeling (Klohs et al., 2012).”

    From Early Alterations in Functional Connectivity and White Matter Structure in a Transgenic Mouse Model of Cerebral Amyloidosis (2014) · cites this paper as Merlini et al., 2011

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Authors
Merlini, M., Meyer, E. P., Ulmann-Schuler, A., & Nitsch, R. M.
Affiliations
  • Gladstone Institutes (US)
  • University of Zurich (CH)
Corresponding author
  • Merlini, Mario
  • Nitsch, Roger M.
ORCID
Merlini, Mario
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2011-06-19
Volume
122
Issue
3
Pages
293-311
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-011-0834-y
PMC
PMC3168476
OpenAlex
W2070251027
Cited by
225
References
67
Citations by year
2026: 10 · 2025: 19 · 2024: 11 · 2023: 18 · 2022: 24 · 2021: 26 · 2020: 18 · 2019: 13 · 2018: 10 · 2017: 12 · 2016: 15 · 2015: 13 · 2014: 8 · 2013: 19 · 2012: 7
FWCI
7.85
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Acta Neuropathologica (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • National Science Foundation
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (112616, 3200B0)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
Keywords
amyloid-beta, Alzheimer's disease, cerebrovascular dysfunction, astrocyte dysfunction, blood-brain barrier, GLUT1, lactate transport, neurovascular uncoupling, cerebral blood flow, vascular smooth muscle cells, amyloid precursor protein, brain metabolism
MeSH terms
Monocarboxylate Transport Protein 1, Animals, Astrocytes, Basement Membrane, Blood-Brain Barrier, Brain, Cerebral Arteries, Cerebrovascular Disorders, Disease Models, Animal, Endothelium, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Glucose, Hemorrhage, Humans, Laminin, Mice, Transgenic, Microscopy, Electron, Scanning, Muscle, Smooth, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Cerebral Amyloid Angiopathy, Microdialysis, Disease Progression, Cell Culture Techniques, Platelet Endothelial Cell Adhesion Molecule-1, Monocarboxylic Acid Transporters, Symporters, Lactase, Dystroglycans, Glucose Transporter Type 1, Mice, Plaque, Amyloid

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