In Aging Brain, Blood-Brain Barrier Starts Leaking in Hippocampus

As any plumber will tell you, if you want to plug a leak, first you have to find it. Leaks in the thousands of blood vessels that infiltrate the central nervous system are no exception. Researchers have long suspected that a breached blood-brain barrier increases the risk for neuronal damage and cognitive decline, but where that breach first occurs has been a mystery. Now, in the January 21 Neuron, researchers led by Berislav Zlokovic at the University of Southern California, Los Angeles, report that in older adults the blood-brain barrier first becomes compromised in subdivisions of the hippocampus. In people with mild cognitive impairment, those leaks are worse. The findings suggest that damage to the barrier puts people at risk of future dementia.

Working with colleagues at USC, and other institutions in the LA area, Zlokovic used dynamic contrast-enhanced MRI to measure the permeability of the blood-brain barrier. Oncologists pioneered DCE-MRI to spot blood vessels invading soft tumors. The method relies on a contrast agent that normally cannot pass through capillaries, and it has high spatial resolution.

First author Axel Montagne and colleagues imaged 12 different regions of the brain in cognitively normal young and old adults, and in older adults with mild cognitive impairment. They found that the BBB became more permeable as people aged, and even leakier in those with MCI. The leakage was not generalized, but started specifically in the hippocampus. It correlated with damage to pericytes, specialized cells that seal blood vessels in the brain and protect neurons from toxins in the plasma, and occurred in the absence of changes to cerebrospinal fluid levels of Aβ or tau. Zlokovic will discuss the findings in an Alzforum webinar on February 17.—Tom Fagan

Comments

  1. This is a very interesting concept. Almost three decades ago, we postulated the same hypothesis, based on histologic analysis of aged brains, demonstrating a blood brain barrier (BBB) breakdown and leakage of serum proteins in aged (but not young) human brain (Pappolla and Andorn, 1987). We also presented a potential mechanism as to how such BBB failure may contribute to age related neurodegeneration (Andorn et al., 1986; Andorn and Pappolla, 1989).

    References:

    Pappolla MA, Andorn AC. Serum protein leakage in aged human brain and inhibition of ligand binding at alpha 2-adrenergic and cholinergic binding sites. Synapse. 1987;1(1):82-9. PubMed.

    Andorn AC, Pappolla MA, Fox H, Klemens FK, Martello PA. Human serum Cohn fraction IV (alpha-globulin [correction of globin] enriched) inhibits ligand binding at neurotransmitter receptors in human brain. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4572-5. PubMed.

    Andorn AC, Pappolla MA. Serum protein interactions with neurotransmitter receptors: implications for Alzheimer's disease. Prog Clin Biol Res. 1989;317:695-701. PubMed.

    View all comments by Mike Miguel Pappolla

  2. The reason for a leaky blood-brain barrier (BBB) with aging may well rest with how dysregulated the HPG axis becomes after menopause and during andropause. We have previously demonstrated that changes in the concentration of sex hormones (gonadotropins, sex steroids) promote the loss of selective permeability of the BBB (Wilson et al., 2009). The hippocampus is rich in luteinizing hormone receptors, which might explain why changes are first seen in this structure. Gonadotropins are well known to regulate the vasculature (during implantation of the blastocyst, for example).

    References:

    Wilson AC, Clemente L, Liu T, Bowen RL, Meethal SV, Atwood CS. Reproductive hormones regulate the selective permeability of the blood-brain barrier. Biochim Biophys Acta. 2008 Jun;1782(6):401-7. Epub 2008 Mar 14 PubMed.

    View all comments by Craig Atwood

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References

Webinar Citations

  1. Leaky Blood-Brain Barrier a Harbinger of Alzheimer's?

Further Reading

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Primary Papers

  1. Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, Toga AW, Jacobs RE, Liu CY, Amezcua L, Harrington MG, Chui HC, Law M, Zlokovic BV. Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015 Jan 21;85(2):296-302. PubMed.

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