Scientists in the U.S. have identified mechanisms that could underpin the earliest stages of about 50% of all dementias, including Alzheimer’s disease (AD), well before the telltale accumulation of protein clumps and tangles in the brain. Researchers at the Keck School of Medicine, University of Southern California (USC) used a combination of mouse models, magnetic resonance imaging (MRI), viral-based tract tracing, and behavioral and tissue analysis to show how the death of pericytes in the smallest brain blood vessels leads to a leaky blood–brain barrier (BBB), which reduces blood flow and allows the accumulation of blood-derived, toxic fibrinogen in the brain. The chain of events caused by the death of pericytes links small vessel disease with white matter disease, which are associated with AD and dementia in the elderly.

The results suggest that the BBB could represent a new target for treating or preventing AD, according to Berislav Zlokovic, M.D., Ph.D., and colleagues. “Many scientists have focused their AD research on the buildup of toxic amyloid and tau proteins in the brain, but this study and others from my lab show that the problem starts earlier—with leaky blood vessels in the brain,” comments Dr. Zlokovic, who holds the Mary Hayley and Selim Zilkha Chair in Alzheimer's Disease Research at the Keck School of Medicine. “The collapse of pericytes—gatekeeper cells that surround the brain's smallest blood vessels—reduces myelin and white matter structure in the brain. Vascular dysfunctions, including blood flow reduction and BBB breakdown, kick off white matter disease.”

The researchers report on their findings in Nature Medicine, in a paper entitled “Pericyte Degeneration Causes White Matter Dysfunction in the Mouse Xentral Nervous System.”

White-matter disease is characterized by the loss of myelin and the death of axons and myelin-producing oligodendrocytes. The disease is also associated with small-vessel disease and dementia in the elderly, the authors note. “Individuals with AD develop early white-matter changes, with loss of oligodendrocytes and axons being concomitant with cerebral vessel pathology, loss of vascular integrity and blood-flow reductions.” However, the authors write, the biological mechanisms linking small-vessel disease with white-matter disease haven’t previously been understood.”Despite the prevalence and clinical importance of age-related white-matter disease associated with small-vessel disease, the underlying biological mechanisms remain elusive.”

To investigate the underlying causes of white matter disease, the Keck School of Medicine team focused on brain capillary pericytes that are embedded in the walls of the smallest blood vessels and control microvascular functions in the brain, including BBB permeability and cerebral blood flow. Previous research has demonstrated pericyte death in AD and in other disorders, including mild dementia and stroke. However, the researchers acknowledge, “the role of pericytes in the pathogenesis of these disorders, particularly the white-matter lesions, remains poorly understood.”

The team first analyzed brain tissue from postmortem AD patients, and found that there was about 50% loss of pericyte coverage and a threefold higher accumulation of blood-derived fibrinogen deposits in key white-matter regions of these individuals when compared with healthy brain tissue. The accumulation of fibrinogen, which is toxic in the brain, indicated capillary leakage and loss of vascular integrity. 

Working with a pericyte-deficient mouse model, the team then demonstrated that pericyte loss was associated with reduced cerebral blood flow and capillary density and 10 times greater accumulation of fibrinogen in the corpus callosum of animals by 12 to 16 weeks of age. The pericyte-deficient mice also exhibited loss of myelin and oligodendrocytes and axon degeneration. “Our observations suggest that once pericytes are damaged, blood flow in the brain reduces like a drain that is slowly getting clogged,” said Angeliki Maria Nikolakopoulou, Ph.D., co-first author of the study and assistant professor of research in physiology and neuroscience at the USC Zilkha Neurogenetic Institute. 

The results may mean that white matter disease in humans could feasibly begin at 40 years of age, comments first study author Axel Montagne, Ph.D., an assistant professor of research in physiology and neuroscience at the Zilkha Neurogenetic Institute, USC Keck School of Medicine. “Pericytes are compromised early on….Think of it as hair clogging a drain over time. Once the drain is clogged, cracks begin forming in the 'pipes' or brain's blood vessels. White matter frays and brain connections are disrupted. That's the beginnings of dementia.”

Pericyte-deficient mice also performed less well in a raft of behavioral tests, such as simple and complex running wheels. The first behavioral problems were observed by 12 to 16 weeks of age and became more evident with increasing age as white matter loss also increased. “”The mice deficient in pericytes function slower because there are structural changes in their white matter and a loss of connectivity among neurons,” Zlokovic notes.

Importantly, treating pericyte-deficient animals with a snake venom enzyme that is known to reduce fibrinogen levels in the brains of AD mouse models resulted in improvements in BBB integrity, better pericyte coverage in the corpus callosum, improved brain blood flow, and reduced fibrin deposits in the white matter. MRI analysis showed large structural improvements in the white matter of snake venom enzyme–treated animals. Pericyte-deficient mice that were genetically engineered to also lack fibrinogen exhibited improved BBB integrity, white matter volume, increased numbers of oligodendrocytes, and better blood flow. In contrast, pharmacologically increasing fibrinogen levels in these animals had the opposite effect.

“We demonstrated that controlling fibrinogen levels can, in a mouse model, reverse or slow white matter disease, the harbinger to dementia,” says Montagne.

“These data suggest that accumulation of white-matter fibrin(ogen) provides an important pathogenic link to pericyte loss, microvascular dysfunction, white matter pathology and oligodendrocyte loss,” the authors conclude. “…our findings may have important implications for the pathogenesis and treatment of small-vessel disease and age-related white-matter disease, and suggest pericytes as a trigger, and potential therapeutic target, for white-matter disease.”

“Our study provides proof that targeting fibrinogen and limiting these protein deposits in the brain can reverse or slow white matter disease,” Zlokovic notes. “It provides a target for treatment, but more research is needed. We must figure out the right approach….Perhaps focusing on strengthening the BBB integrity may be an answer because you can't eliminate fibrinogen from blood in humans. This protein is necessary in the blood. It just happens to be toxic to the brain.”

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