Leaky Blood-Brain Barrier a Harbinger of Alzheimer's?
To sate the brain’s voracious hunger for energy, thousands of capillaries deliver blood and oxygen to every sulcus and gyrus, and the white and gray matter in between. Herein lies a problem. The delicate cells of the brain must be protected from the flotsam and jetsam, homemade or foreign, coursing through the blood stream. Enter the blood-brain barrier (BBB), a cell-based seal that has evolved to keep our most precious cells in blissful isolation. What if that barrier breaks down?
On Tuesday, February 17, Berislav Zlokovic discussed his latest findings. Borrowing from oncology, Zlokovic and colleagues used dynamic contrast-enhanced MRI, an imaging method that quantifies blood flow, to obtain high resolution maps of BBB permeability. DCE-MRI uses a contrast agent that normally cannot cross the BBB. They show that as people age, the barrier begins to leak in the hippocampus, a region key to learning and memory and one of the first to degenerate in Alzheimer's disease. In people who have mild cognitive impairment, the hippocampal BBB falters even more. Tammie Benzinger, Roderick Corriveau, and Costantino Iadecola joined Zlokovic for a panel discussion.
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To protect the central nervous system, the specialized cells of the blood-brain barrier form a seal around capillaries and larger vessels, allowing oxygen and nutrients to pass, but stopping proteins, cells, pathogens, and other potential toxins from damaging neurons and glia in the brain. Breach of the BBB can be catastrophic, as in subdural hematoma, but it can also be slow and insidious. Some scientists believe that over time, a leaky barrier puts people at risk for Alzheimer's. Microbleeds in the brain are common in normal aging, while superficial siderosis, a condition where blood proteins seep into the brain parenchyma, crops up more often in people with AD than in healthy controls (see Cullen et al., 2005; Goos et al., 2009; and Feb 2014 news). Iron, possibly from the breakdown of hemoglobin, accumulates in the brain in AD, particularly in the hippocampus, while blood albumin in the cerebrospinal fluid of AD patients at risk for vascular disease suggests that the barrier has been compromised (see Raven et al., 2013; Blennow et al., 1990).
Brain imaging studies hint that the BBB becomes porous in people with dementia, particularly those who also have cardiovascular disease (see van de Haar et al., 2015, for a review). However, most imaging modalities cannot pinpoint precisely where the leaks are. Working with colleagues at the University of Southern California and other institutions in the Los Angeles area, Zlokovic's group has boosted spatial and temporal resolution with the help of dynamic contrast-enhanced magnetic resonance imaging, a method used to image the way blood vessels invade tumors. DCE-MRI visualizes exactly where a contrast agent crosses the BBB. First author Axel Montagne and colleagues took DCE-MRI scans of six healthy young people, 18 older folks who were cognitively normal, and 21 older adults who had mild cognitive impairment (MCI). The researchers measured BBB permeability in 12 specific areas of the brain, including parts of the cortex, hippocampus, and subcortex. They did lumbar punctures to correlate BBB permeability with CSF markers of barrier damage, Alzheimer’s, and neurodegeneration.
Montagne found that regardless of cognitive status, the BBB in the CA1 and dentate gyrus subdivisions of the hippocampus became porous with age. In all other areas of the brain studied, the BBB looked intact. In people with MCI, the hippocampal barrier was even more permeable, and the damage extended to the CA3 of the hippocampus as well.
Biomarker analysis supported the idea that the BBB was leaking in people with MCI, because their CSF contained 30 percent more blood-derived albumin. Their CSF also accumulated twice as much soluble platelet-derived growth factor β (sPDGFβ). This factor is produced by pericytes, cells of the BBB that form tight seals around capillaries. In this paper, the researchers report that isolated human pericytes shed the protein when deprived of oxygen or exposed to the Aβ. Interestingly, the authors found no markers in the CSF to indicate damage to endothelial cells that also surround blood vessels, hinting that damage to the BBB starts with pericytes.
Furthermore, both the normal controls and the MCI volunteers had normal amounts of tau and phospho-tau in their CSF, suggesting no signs of neurodegeneration. They also had normal levels of CSF Aβ42, which falls in preclinical AD. All told, the findings suggest that damage to the blood-brain barrier, perhaps as a fact of normal aging, could contribute to cognitive decline. Future studies in larger samples will clarify the relationship of this process to Alzheimer's disease.—Tom Fagan
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Berislav Zlokovic, M.D., Ph.D.
University of Southern California
Tammie Benzinger, M.D., Ph.D.
Washington University in St. Louis, School of Medicine
Costantino Iadecola, M.D.
Weill College Medicine
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).
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.
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