APOE Stabilization by Exercise Prevents Aging Neurovascular Dysfunction and Complement Induction
Open accessAbstract
Aging is the major risk factor for neurodegenerative diseases such as Alzheimer's disease, but little is known about the processes that lead to age-related decline of brain structures and function. Here we use RNA-seq in combination with high resolution histological analyses to show that aging leads to a significant deterioration of neurovascular structures including basement membrane reduction, pericyte loss, and astrocyte dysfunction. Neurovascular decline was sufficient to cause vascular leakage and correlated strongly with an increase in neuroinflammation including up-regulation of complement component C1QA in microglia/monocytes. Importantly, long-term aerobic exercise from midlife to old age prevented this age-related neurovascular decline, reduced C1QA+ microglia/monocytes, and increased synaptic plasticity and overall behavioral capabilities of aged mice. Concomitant with age-related neurovascular decline and complement activation, astrocytic Apoe dramatically decreased in aged mice, a decrease that was prevented by exercise. Given the role of APOE in maintaining the neurovascular unit and as an anti-inflammatory molecule, this suggests a possible link between astrocytic Apoe, age-related neurovascular dysfunction and microglia/monocyte activation. To test this, Apoe-deficient mice were exercised from midlife to old age and in contrast to wild-type (Apoe-sufficient) mice, exercise had little to no effect on age-related neurovascular decline or microglia/monocyte activation in the absence of APOE. Collectively, our data shows that neurovascular structures decline with age, a process that we propose to be intimately linked to complement activation in microglia/monocytes. Exercise prevents these changes, but not in the absence of APOE, opening up new avenues for understanding the complex interactions between neurovascular and neuroinflammatory responses in aging and neurodegenerative diseases such as Alzheimer's disease.
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Transgenic mice lacking Apoe develop an early BBB breakdown.
“Transgenic mice lacking Apoe also develop an early BBB breakdown (60, 99, 147, 187, 226, 233, 406, 426, 437, 554), indicating that APOE is essential for maintaining BBB integrity.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [554]
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RNA-Seq Mouse Brain Regions Expression Data Analysis: Focus on ApoE Functional Network
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Self-citation
- Authors
- Soto, I., Graham, L. C., Richter, H. J., Simeone, S. N., Radell, J. E., Grabowska, W., Funkhouser, W. K., Howell, M. C., & Howell, G. R.
- Affiliations
- Jackson Laboratory (US)
- Tufts University (US)
- Corresponding author
- Howell, Gareth R.
- ORCID
- Venue
- PLOS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-10-29
- Volume
- 13
- Issue
- 10
- Pages
- e1002279
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- PMC
- PMC4626092
- OpenAlex
- W2172610621
- Cited by
- 140
- References
- 98
- Citations by year
- 2026: 5 · 2025: 15 · 2024: 18 · 2023: 19 · 2022: 17 · 2021: 12 · 2020: 11 · 2019: 16 · 2018: 7 · 2017: 9 · 2016: 8 · 2015: 3
- FWCI
- 4.81
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Biology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Rowan Digitals Works (Rowan University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- National Institutes of Health (NIH-R01)
- National Eye Institute (R01EY021525, NIH R01 EY021525)
- National Institute of General Medical Sciences (P20GM103423)
- National Institute of Neurological Disorders and Stroke (R25NS078795)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- apolipoprotein E, aerobic exercise, aging, neurovascular dysfunction, complement activation, C1QA, microglia, monocytes, neuroinflammation, astrocytes, pericyte loss, basement membrane, vascular leakage, synaptic plasticity, Alzheimer's disease, ApoE-deficient mice
- MeSH terms
- Neurovascular Coupling, Aging, Animals, Apolipoproteins E, Astrocytes, Blood-Brain Barrier, Complement Activation, Endothelium, Vascular, Female, Homozygote, Mice, Inbred C57BL, Monocytes, Motor Activity, Mutation, Nerve Tissue Proteins, Neuronal Plasticity, Vascular Diseases, Complement C1q, Gene Expression Regulation, Developmental, Neurodegenerative Diseases, Microscopy, Electron, Transmission, Protein Stability
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