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Blocking protein that impairs brain’s clean-up crew improves old mice’s smarts

Brain cells called microglia keep brains young by eliminating accumulations of protein debris. But their garbage-colllection ability fades with age.

Stanford neuroscientist Tony Wyss-Coray, PhD, has been working for several years on the question of what causes the brain to lose its acuity with advancing age. One focus of his research has been a class of brain cells called microglia, which serve as the brain's immune cells.

A less-vaunted microglial function is more akin to that of a garbage crew. Among the many different things microglia do to keep the brain healthy is scarfing up bits of cellular debris and protein deposits that build up like so much dandruff in the course of normal metabolic activity.

Bits of myelin debris -- remnants of decaying nerve-cell coatings that, by providing electrical insulation, speed the transmission of impulses along nerve tracts -- commonly accumulate in aging brains. Aging-associated aggregation of a protein fragment called beta-amyloid into gummy deposits in the brain are considered a hallmark of Alzheimer's disease. Likewise with clumps of yet another substance, alpha-synuclein, associated with Parkinson's disease.

These accumulations occur over time largely because, as I wrote in my news release about a study published in Nature by Wyss-Coray and his colleagues:

[T]he garbage-collecting performance of microglia diminishes in aging brains. Why this happens, and the extent to which the faulty garbage service is actually responsible for age-related cognitive losses, are unclear. But it's a decent bet that one way or another, microglial malperformance plays a role in neurodegeneration.

In a series of sophisticated experiments, Wyss-Coray's team identified a single protein called CD22 that, in the brain, is found only on the surfaces of microglial cells; becomes increasingly abundant with increasing age (in mice, at least); and, when activated, profoundly impairs these cells from performing their debris-cleanup role.

Then, the researchers conducted another set of experiments. Into one side of mice's brains, they injected specialized proteins (called antibodies) capable of blocking CD22's activity without otherwise disrupting brain function. Into the mirror-image spot on the other side of the mice's brains, they injected otherwise identical antibodies that, however, lacked the ability to block CD22.

Along with the antibodies, the scientists injected bits of myelin -- like sprinkling some confetti around to test a new vacuum cleaner. On inspection two days later, the myelin debris was much less prevalent on the side of mice's brains where "working" antibodies rather than "dummy" antibodies to CD22 had been injected.

The same thing happened when instead of myelin debris, the researchers injected beta-amyloid or alpha-synuclein, the Alzheimer's- and Parkinson's-associated substances.

In all three cases, microglia exposed to CD22-blocking antibodies outperformed their fellow microglia on the opposite side of the brain in ingesting the neurodegeneration-linked substances.

Then, the researchers lengthened the period of exposure from 48 hours to a full month. From my news release:

They reconfigured their injection technique to provide continuous CD22-blocking antibody infusion on both sides of the brain over this period. ... [O]ld mice receiving these infusions outperformed control mice of the same age on two different tests of learning and memory that are commonly used to assess mice's cognitive ability.

"The mice became smarter," Wyss-Coray told me. "Blocking CD22 on their microglia restored their cognitive function to the level of younger mice."

He thinks CD22 could prove to be a brand-new target for treatment of neurodegenerative diseases.

Photo by The Creative Exchange

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