Many cases of dementia are characterized by toxic amyloid plaques and tangles in the brain, most notably Alzheimer’s disease. That’s why so many experimental Alzheimer’s drugs target brain plaques. But researchers at the University of Southern California’s Keck School of Medicine believe the hunt for Alzheimer’s cures should start much earlier in the formation of the disease—with tiny blood vessels in the brain that start to break down as early as age 40.
About half of all dementias start when these blood vessels malfunction, allowing toxic substances to flood the brain and disrupt communications. And many people with that disorder, called “small vessel disease,” also have “white matter disease,” which occurs when the protective myelin around brain neurons wears away, causing a slowdown of thinking, memory and balance. The USC team has discovered what starts that process, according to a statement from the university.
The culprit is damaged pericytes, which are cells that act as gatekeepers surrounding the diminutive blood vessels in the brain. This pericyte collapse reduces white matter and myelin, according to Berislav Zlokovic, a USC Alzheimer’s researcher and senior author of the study, which was published in Nature Medicine. “Vascular dysfunctions, including blood flow reduction and blood-brain barrier breakdown, kick off white matter disease," he said in the press release.
When pericytes break down, they release a blood protein called fibrinogen, which normally helps blood to clot. But too much fibrinogen in the brain is toxic, as the protein causes white matter and critical brain structures to die. The USC team showed in mouse models that controling fibrinogen levels can reverse white matter disease.
They also studied mice lacking pericytes, using MRI imaging to study blood vessel leakage in the brain. They discovered 50% increased leaking in mice that were 36 to 48 weeks old, which translates to roughly age 70 in people. And when the mice were as young as 12 weeks old, they had 10 times more fibrinogen than control animals. They were also slower when it came time to learn how to run on an exercise wheel that had been slightly altered.
"The mice deficient in pericytes function slower because there are structural changes in their white matter and a loss of connectivity among neurons," Zlokovic said.
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The so-called amyloid hypothesis of Alzheimer’s—the notion that the disease starts with brain plaques—has driven much of the drug development of recent years, but with limited success. Eli Lilly’s solanezumab and Pfizer's bapineuzumab are among the experimental amyloid-targeting Alzheimer’s treatments that have failed.
Many research teams have been looking for ways to target impaired brain signaling instead of amyloid. In December, for example, a team of British researchers announced that combining the growth factors GLP-1, GIP and glucagon reversed memory loss in mouse models of Alzheimer’s. The treatment, originally developed for Type 2 diabetes, seemed to slow the loss of nerve cells and preserve their functioning.
The USC team believes their pericyte research could provide the basis for a new class of Alzheimer’s treatments. When they studied cells taken from human Alzheimer’s patients postmortem, they observed half as many of the gatekeeper cells as were present in healthy brains, according to the statement. They also found three times more fibrinogen.
That said, eliminating fibrinogen is not an option because of its importance in preserving blood function, Zlokovic said. But if the correct approach can be identified, “targeting fibrinogen and limiting these protein deposits in the brain can reverse or slow white matter disease," he said.