Blood vessels feed the ever-hungry brain, so naturally they have a critical role to play in keeping it healthy or letting it starve. At the third annual Zilkha Symposium on Alzheimer Disease & Related Disorders, held April 15, 2016, at the University of Southern California in Los Angeles, three researchers presented the latest on this topic, which is starting to get traction in AD research. USC’s Berislav Zlokovic, who co-organized the conference, discussed how aging and ApoE4 genotype conspire to cause leaks in the blood-brain barrier. Costantino Iadecola of the Weill Cornell Medical College in New York presented work on how tau blunts the ability of neurons to call in more blood flow when they need additional oxygen. Christer Betsholtz of Uppsala University in Sweden focused on the biology of pericytes, the little contractile cells that envelop blood vessels and manage flow rates.
The arteries, veins, and capillaries that pervade the brain have started to receive attention from dementia researchers in recent years. “As our knowledge advances, the thinking and focus of the science of cognitive decline has expanded to include blood vessels,” said Roderick Corriveau, a program director at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland. An integrated view of brain function that includes neurons, glia, the vasculature, and immune cells that cross the blood-brain barrier offers a more realistic understanding of neurodegeneration, Corriveau said. In 2014, the National Institutes of Health started using the term “vascular contributions to cognitive impairment and dementia” to categorize such studies. “That was the first recognition of VCID as a scientific field,” Corriveau said. Its scope includes the aging neurovascular unit and its failure to cope with biological insults due to vascular disease, Alzheimer’s biology, metabolic disease, and immune stressors (see Corriveau et al., 2016; Snyder et al., 2014; Apr 2016 conference news).
Tau Acts Alone
Dysfunction of the vasculature might well contribute to the onset or progression of AD, Zlokovic told Alzforum. If so, how might tau interact with the brain’s vasculature? Iadecola’s group has developed a system in which to study blood vessel activity in the mouse whisker barrel cortex. Tickle a whisker, and cortical neurons in its projection area should activate, stimulating more blood delivery. By opening a cranial window above the whisker barrel cortex, the researchers can drip in compounds such as vasodilators or muscle relaxants, and observe how the blood flow changes in different conditions (May 2014 conference news). Scientists already know that Aβ affects diverse aspects of cerebral circulation, Iadecola told Alzforum. It effectively leads to a low-oxygen, high blood-pressure situation in the brain akin to that in a person with hypertension or diabetes.
In the new work, the lab turned its attention to tau. “There is increasing evidence that there is a problem with blood flow in the pure diseases of tau,” Iadecola told Alzforum. For example, a recent study of autopsy brains suggested that tau pathology remodels blood vessel walls (Merlini et al., 2016).
The researchers examined two models of tauopathy, the rTg4510 mouse expressing a repressible tau-P301S; and the PS19 mouse that expresses the same mutant gene under control of the prion promoter, which is active in neurons. Results were similar in both lines. When the scientists tweaked their whiskers, blood flow to the whisker barrel cortex should have risen, but this response was impaired.
Iadecola suspected the problem might be in the activity of NMDA receptors. Upon stimulation, these receptors normally release nitric oxide, which dilates blood vessels. When the researchers inhibited NMDA receptors in the mutant tau mice, manipulation did not affect their response to whisker stimulation, because that pathway was already inactive. “Most likely the coupling between the NMDA receptor and the nitric oxide that is needed to increase flow is not there,” Iadecola said.
In people with Alzheimer’s, the combined actions of Aβ and tau likely alter vascular regulation, starving neurons of oxygen when they need it most, Iadecola said. He is now investigating the mechanisms of Aβ and tau action on the vasculature in more detail, asking whether they work in concert or independently.
If the brain’s vasculature is damaged in Alzheimer’s, how would doctors know? Zlokovic gave an overview of his ongoing work on just such a biomarker: brain blood flow measured by a technique called dynamic contrast-enhanced MRI. The contrast agent, containing gadolinium, cannot cross the blood-brain barrier unless the barrier is leaky. Using this method, Zlokovic and colleagues previously reported that the barrier starts to become porous with age in cognitively healthy people, and even more so in those with mild cognitive impairment (see Feb 2015 webinar). At the Zilkha conference, Zlokovic told attendees he has preliminary evidence that this permeability at the barrier might have consequences for connectivity of neurons. He is also following up, in people, on a previous mouse study that indicated the ApoE4 genotype makes the barrier more porous (Bell et al., 2012).
“Gadolinium-enhanced imaging of permeability of the blood-brain barrier is a potential biomarker, for both compromise of the barrier and the advent of cognitive impairment and dementia during aging. It is a potentially powerful new tool that I hope is explored further,” said Corriveau.
Iadecola agreed, saying indicators of a leaky blood-brain barrier could be particularly important as an early marker, well before symptoms arise, when the disease process is underway in the background. “That is going to be the future in Alzheimer’s disease,” he said. In addition to the MRIs, Zlokovic noted to Alzforum that he has discovered fluid biomarkers, particularly PDGF receptor β in the cerebrospinal fluid, that can flag barrier breakdown.
Contractile pericytes are crucial to maintaining the blood-brain barrier. If they malfunction in Alzheimer’s, then scientists will need to understand the details of those defects in order to find ways to repair them, Iadecola said. But even before this step, scientists still need to more fully comprehend the normal inner workings of a healthy pericyte. For example, little is known about how a pericyte differs from the endothelial cells that line the brain’s blood vessels. That is where Betsholtz’s work on their basic biology comes in. Betsholtz is profiling pericytes by RNA sequencing of single cells, and analyzing their proteome. Although these cells are very interesting, Betsholtz told Alzforum, researchers still do not understand if they play a major role in AD or are bystanders.
Zlokovic told Alzforum his group also is developing methods to study this question, using a mouse model that expresses the Cre enzyme specifically in pericytes. “This new model will allow us to express or delete any genes specifically from pericytes,” he said. “We can use it to address many questions.”
Pericytes and the rest of the vasculature are likely to get plenty of attention in the future, scientists said. “The neurovascular unit is probably more important than we think,” commented Philip Scheltens of VU University Medical Center in Amsterdam.—Amber Dance
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Research Models Citations
- Corriveau RA, Bosetti F, Emr M, Gladman JT, Koenig JI, Moy CS, Pahigiannis K, Waddy SP, Koroshetz W. The Science of Vascular Contributions to Cognitive Impairment and Dementia (VCID): A Framework for Advancing Research Priorities in the Cerebrovascular Biology of Cognitive Decline. Cell Mol Neurobiol. 2016 Mar;36(2):281-8. Epub 2016 Apr 19 PubMed.
- Snyder HM, Corriveau RA, Craft S, Faber JE, Greenberg SM, Knopman D, Lamb BT, Montine TJ, Nedergaard M, Schaffer CB, Schneider JA, Wellington C, Wilcock DM, Zipfel GJ, Zlokovic B, Bain LJ, Bosetti F, Galis ZS, Koroshetz W, Carrillo MC. Vascular contributions to cognitive impairment and dementia including Alzheimer's disease. Alzheimers Dement. 2014 Dec 12; PubMed.
- Merlini M, Wanner D, Nitsch RM. Tau pathology-dependent remodelling of cerebral arteries precedes Alzheimer's disease-related microvascular cerebral amyloid angiopathy. Acta Neuropathol. 2016 May;131(5):737-52. Epub 2016 Mar 17 PubMed.
- Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Holtzman DM, Betsholtz C, Armulik A, Sallstrom J, Berk BC, Zlokovic BV. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 2012 May 24;485(7399):512-6. PubMed.
- Park L, Zhou J, Zhou P, Pistick R, El Jamal S, Younkin L, Pierce J, Arreguin A, Anrather J, Younkin SG, Carlson GA, McEwen BS, Iadecola C. Innate immunity receptor CD36 promotes cerebral amyloid angiopathy. Proc Natl Acad Sci U S A. 2013 Feb 19;110(8):3089-94. PubMed.
- Park L, Wang G, Moore J, Girouard H, Zhou P, Anrather J, Iadecola C. The key role of transient receptor potential melastatin-2 channels in amyloid-β-induced neurovascular dysfunction. Nat Commun. 2014 Oct 29;5:5318. PubMed.
- Bell RD, Winkler EA, Sagare AP, Singh I, LaRue B, Deane R, Zlokovic BV. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron. 2010 Nov 4;68(3):409-27. PubMed.
- Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci. 2011 Dec;12(12):723-38. PubMed.
- Zhao Z, Nelson AR, Betsholtz C, Zlokovic BV. Establishment and Dysfunction of the Blood-Brain Barrier. Cell. 2015 Nov 19;163(5):1064-78. PubMed.
- Montagne A, Nation DA, Pa J, Sweeney MD, Toga AW, Zlokovic BV. Brain imaging of neurovascular dysfunction in Alzheimer's disease. Acta Neuropathol. 2016 May;131(5):687-707. Epub 2016 Apr 1 PubMed.