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The role of neurovascular health in aging

Image credit: https://www.nature.com/articles/nrneurol.2017.188?WT.feed_name=subjects_neurodegenerative-diseases

Andrew Pan Nov 29, 2020

It is well known that the risk of neurodegenerative diseases is greatly increased as one ages. Alzheimer's and Parkinson's are some of the most prevalent diseases one may develop once they are 60. Relatively rarer diseases, such as ALS, also count age as a big risk factor. One underappreciated factor in all these diseases is the contribution of neurovascular degeneration.

To discuss the importance of the blood-brain barrier in neurodegeneration, one must first be acquainted with its normal physiological function and anatomy. The blood-brain barrier is interchangeable with the vascular network which feeds the brain, but the impermeability relative to other vascular beds in the body makes it particularly unique. This “tightness” achieved by tight junctions such as ZO-1 between adjacent endothelial cells makes physiological sense, the brain must be particularly careful of what entities are allowed to enter the brain parenchyma. The endothelial cells forming the barrier are supported by glial cells in the brain called astrocytes, alongside multi-functional mural cells called pericytes that wrap around the endothelial cells. Together, these three cells form the basic neurovascular unit, although some groups also have argued that neurons belong to part of this group.

Moving back to the discussion on how neurovascular degeneration may lead to neurodegeneration – one of the easiest ways to see how this may be true is how factors in the blood itself can be neurotoxic. For instance, serum albumin can lead to astrocytes taking on a neurotoxic reactive phenotype. Free heme also can trigger an inflammatory microglia response. What is most interesting is the finding that APOE4, a very prominent allele that is associated with increased Alzheimer’s risk relative to the alleles APOE3 and APOE2, can cause blood-brain barrier degeneration by impeding normal pericyte function. Studies in human patients have also found that the blood-brain barrier have found increased blood-brain barrier permeability to gadolinium, specifically in the hippocampus using MRI studies. Indeed, cerebral microbleeds are frequently seen in Alzheimer’s patients and APOE4 positive individuals. Studies from post-mortem brain tissue of Alzheimer’s patients have found that there is an increased accumulation of serum proteins such as fibrinogen and albumin in the prefrontal cortex and hippocampus.

This leads to the question of, is this a chicken or the egg situation? Does the onset of disease lead to vascular degeneration which then creates a positive feedback loop to aggravate disease pathology, or does vascular degeneration come first? This is an interesting question that will need more research to conclusively demonstrate, but one interesting study published recently in Nature medicine found that Blood-brain barrier breakdown actually occurs independently and irrespective of amyloid-beta and tau pathologies which are canonically recognized as part of Alzheimer’s. Furthermore, this breakdown is found in patients with early higher cognitive dysfunction. This suggests at least that amyloid-beta and tau do not contribute to degeneration. A potential mechanism of action is that early degeneration may in fact lead to the accumulation of neurotoxic factors mentioned earlier, triggering the build-up/altered trafficking of amyloid and tau. For example, LRP-1 is a protein found in the blood-brain barrier that is responsible for trafficking Amyloid-beta out of the brain, and LRP-1 activity is decreased during vascular degeneration. Findings from Lee Rubens lab at Harvard discovered that GDF11 may promote neurovascular repair and subsequently, neurogenic rejuvenation.

What are your thoughts? Do you think there’s enough merit to develop some novel therapeutics to promote vascular repair? Or perhaps using a biomaterial hydrogel with rejuvenating factors such as GDF11 approach to attempt some tissue engineering locally at the site of disruption? What about simple lifestyle changes one can make such as exercise or following a proper diet?

[1]Sweeney, M. D., Kisler, K., Montagne, A., Toga, A. W. & Zlokovic, B. V. The role of brain vasculature in neurodegenerative disorders. Nat. Neurosci.21, 1318–1331 (2018).

[2]Sweeney, M. D., Sagare, A. P. & Zlokovic, B. V. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat. Rev. Neurol.14, 133–150 (2018).

[3]Luissint, A. C., Artus, C., Glacial, F., Ganeshamoorthy, K. & Couraud, P. O. Tight junctions at the blood brain barrier: Physiological architecture and disease-associated dysregulation. Fluids Barriers CNS9, 1–12 (2012).

[4]Sharif, Y. et al.Blood brain barrier: A review of its anatomy and physiology in health and disease. Clin. Anat.31, 812–823 (2018).

[5]Abbott, N. J. Astrocyte – endothelial interactions and blood – brain barrier permeability *. 629–638 (2002).

[6]Cho, C. F. et al.Blood-brain-barrier spheroids as an in vitro screening platform for brain-penetrating agents. Nat. Commun.8, (2017).

[7]Armulik, A. et al.Pericytes regulate the blood-brain barrier. Nature468, 557–561 (2010).

[8]Nation, D. A. et al.Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat. Med.25, 270–276 (2019).

[9]Katsimpardi, L. et al.Vascular and Neurogenic Rejuvenation of the Aging Mouse Brain by Young Systemic Factors. Science (80-. ).344, 630–635 (2014).

Creative contributions

Whether GDF11 helps in rejuvenation is debated

Shubhankar Kulkarni
Shubhankar Kulkarni Dec 01, 2020
Evidence for GDF11 showing rejuvenation:
  1. GDF11 also boosted the growth of new blood vessels and neurons in the brain and skeletal muscle at the sites of injuries.
  2. The mouse heterochronic parabiosis model revealed that GDF11 could increase blood vessel volume as well as neurogenesis in old mice. Blood from 15-month-old mice did not decrease neural stem-cell populations in the young brain, whereas older blood (21 months) provoked a detrimental effect.
  3. In another parabiosis study, it was found that satellite cells sorted from aged-heterochronic mice had improved myogenic differentiation capacity as well as lower DNA damage when compared with satellite cells from aged-isochronic controls.
  4. In vitro exposure of aged satellite cells to GDF11 produced dose-responsive increases in satellite cell proliferation and differentiation, suggesting that GDF11 can act directly on satellite cells to alter their function. The treatment of aged mice with daily intraperitoneal injections of recombinant GDF11 for 4 weeks increased numbers of satellite cells with intact DNA.
  5. In a model of muscle injury, GDF11 treatment of aged mice 28 days before the injury and continued for 7 days thereafter restored more youthful profiles of myofiber caliber in regenerating muscle. Aged mice treated with GDF11 also showed increased average exercise endurance and grip strength.
Contrary evidence:
  1. GDF11 mRNA levels rose in rat muscle with increased age.
  2. In vitro experiments showed that GDF11 induces the signaling pathways (SMAD 2/3 and MAPK activation) in primary and immortalized human skeletal muscle cells and that differentiation of human primary myoblasts into myotubes was inhibited by GDF11.
  3. Higher systemic levels of GDF11 were associated with impaired regeneration in young mice, as indicated by a greater number of very small myofibers in the GDF11-treated muscles.
  4. The treatment with GDF11 decreased the growth of adult and aged satellite cell cultures in a dose-dependent manner.
These contradicting results could be due to multiple forms of GDF11 and only one could decrease with age.

[1]Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, et al. Vascular and Neurogenic Rejuvenation of the Aging Mouse Brain by Young Systemic Factors. Science (80- ) [Internet]. 2014 May 9;344(6184):630–4. Available from: https://www.sciencemag.org/lookup/doi/10.1126/science.1251141

[2]Sinha M, Jang YC, Oh J, Khong D, Wu EY, Manohar R, et al. Restoring Systemic GDF11 Levels Reverses Age-Related Dysfunction in Mouse Skeletal Muscle. Science (80- ) [Internet]. 2014 May 9;344(6184):649–52. Available from: https://www.sciencemag.org/lookup/doi/10.1126/science.1251152

[3]Loffredo FS, Steinhauser ML, Jay SM, Gannon J, Pancoast JR, Yalamanchi P, et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell [Internet]. 2013 May 9;153(4):828–39. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23663781

[4]Trendelenburg A, Meyer A, Jacobi C, Feige JN, Glass DJ. TAK-1/p38/nNFκB signaling inhibits myoblast differentiation by increasing levels of Activin A. Skelet Muscle [Internet]. 2012;2(1):3. Available from: http://skeletalmusclejournal.biomedcentral.com/articles/10.1186/2044-5040-2-3

[5]Grens K. Studies Conflict on Regenerative Molecule. The Scientist [Internet]. 2015; Available from: https://www.the-scientist.com/daily-news/studies-conflict-on-regenerative-molecule-35447

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