. APOE Stabilization by Exercise Prevents Aging Neurovascular Dysfunction and Complement Induction. PLoS Biol. 2015 Oct;13(10):e1002279. Epub 2015 Oct 29 PubMed.


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  1. Growing evidence suggests that maintaining a physically active lifestyle may be particularly beneficial in reducing the risk for dementia and Alzheimer's disease. In this paper, Soto et al. convincingly show that exercise in aging mice preserves the integrity and function of the neurovascular unit (NVU) leading to a healthier and “younger-like” brain.

    Using RNA-seq, in combination with histological analyses, Soto and colleagues showed that aging leads to significant deterioration of neurovascular structures, including basement membrane reduction, pericyte loss, and astrocyte dysfunction. Moreover, they show that age-dependent neurovascular decline leads to vascular leakages and blood-brain barrier (BBB) breakdown. Next, they provide important evidence that astrocytic APOE levels decrease in mice with aging that correlates with BBB disruption characterized by perivascular fibrin deposition, pericyte loss, gene expression changes, activation of microglia, and loss of aquaporin-4 from astrocytic endfeet. Interestingly, the authors found that exercise restores brain APOE levels in older mice, which rescues the vascular phenotype. The authors next studied the effects of exercise in APOE-null mice that develop pronounced BBB breakdown as shown by multiple independent laboratories, and show that exercise partially rescues vascular abnormalities in these mice by increasing the number of pericytes, but some BBB leakage, increased numbers of activated microglia, and behavioral deficits still persist.

    Overall, this paper also supports recent findings of age-dependent BBB breakdown in humans and worsening of BBB disruption in early stages of dementia, as we demonstrated using an advanced dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) method (Montagne et al., 2015). Interestingly, increased BBB permeability in elderly humans with mild dementia also correlates with pericyte injury, as shown by increased CSF levels of soluble platelet-derived growth factor receptor β (sPDGFRβ) – a marker of pericyte injury (Sagare et al., 2015). Again, this corroborates the present findings in the aging murine brain.

    Given the critical role of APOE in maintaining normal NVU integrity (Bell et al., 2012), Soto et al. data further extend previous findings by suggesting a link between astrocytic APOE, age-related neurovascular dysfunction, BBB breakdown, and microglia/monocyte activation. Future studies should address whether these findings in aging mice can translate to aging humans at genetic risk for AD carrying APOE4 allele and in APOE4 non-carriers with a lower risk for AD, and whether exercise will help ameliorate neurovascular changes and vascular phenotype during aging in humans.


    . Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015 Jan 21;85(2):296-302. PubMed.

    . Shedding of soluble platelet-derived growth factor receptor-β from human brain pericytes. Neurosci Lett. 2015 Oct 21;607:97-101. Epub 2015 Sep 25 PubMed.

    . Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 2012 May 24;485(7399):512-6. PubMed.

  2. The authors’ findings complement extant literature suggesting that exercise attenuates age-related changes associated with Alzheimer’s disease. The study’s results support a mechanism by which exercise provides resilience to neurovascular decline. The proposed involvement of neuroinflammatory pathways highlights the need for further investigation, in humans, of aberrant immune response and inflammation in AD. Elucidating the biological mechanisms of the protective effects of engagement in physical activity, in humans, on these specific pathways would provide valuable insight for future non-pharmacological interventions for AD.

    Interestingly, the diminishing age-related effects were only observed in APOE-producing animals. These findings extend recent human studies that show an interaction between physical activity and APOE4-carrier status on AD biomarkers. Future studies examining the effects of APOE, exercise, and neurovascular decline on the risk for AD are needed, and may help identify at-risk individuals who would benefit from lifestyle intervention.

  3. This is an incredibly interesting article demonstrating that exercise can limit age-related decline in neurovascular integrity and cognitive function. While it is clear that neurovascular integrity and function decline with age, and that this can lead to declining cognitive function, it is not known what molecular mechanism mediates this pathway or whether lifestyle changes can attenuate this issue. This article shows an important role of exercise in limiting neurovascular decline, demonstrating that indeed environmental and lifestyle changes can influence this process. Furthermore, the authors demonstrate that ApoE, a known susceptibility locus for Alzheimer’s disease, is a key mediator that helps maintain neurovascular integrity through life, linking normal age-related decline with pathophysiology of AD. Therefore, this new finding has important implications for understanding the molecular mechanism of age-related cognitive decline as well as Alzheimer’s disease, and for finding methods to potentially attenuate these processes.

    This study also raises several really interesting questions, most notably, how does ApoE mediate the ability of exercise to regulate neurovascular aging, and how can we harness this to limit age-related cognitive decline as well as the onset and progression of AD? It will be very interesting to identify the sequence of events that leads to disrupted neurovascular integrity and age-related cognitive decline to determine which cell(s) ApoE acts on, and how these signals are then transduced to other neural, vascular, and immune cells. Does ApoE signal to all cells within the neurovascular unit to maintain integrity or does it target one cell type, such as pericytes, which then maintain the integrity of the unit? Which are the critical signaling interactions for the decrease in cognitive function? Which interactions can be targeted by pharmacological intervention? Furthermore, it will be of particular interest to understand how different ApoE isoforms can influence these processes, and how they may go awry in AD.

    View all comments by Richard Daneman

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This paper appears in the following:


  1. Exercise Slows Brain Aging in Mice, with a Little Help from ApoE