New study shows a form of age-related cognitive decline—tied to an immune-system molecule—can be reversed in mice.

Two studies published in 2014 and 2015 — the product of a collaboration between Saul A. Villeda, PhD, a Faculty Fellow at University of California San Francisco (UCSF) and Tony Wyss-Coray, PhD, professor of neurology at Stanford University — provide important insights into the cause of one type type of cognitive decline—and the possibility of reversing its effects. (note: Dr. Wyss-Coray has been previously funded by JDFAF. Read his profile here.)

The research teams found that a blood-borne molecule (beta-2 microglobulin, or B2M, a component of a larger molecule called MHC) which plays an important role in the adaptive immune system, greatly increases as we age, and can act adversely in the brain, in ways not related to immunity—blocking the regeneration of brain cells, thus promoting cognitive decline.

In 2014 study, Villeda and Tony Wyss-Coray showed that connecting the circulatory system of a young mouse to that of an old mouse could reverse the declines in learning ability that typically emerge as mice age.

Over the course of their research, however, the researchers noted an opposite effect—blood from older animals appears to contain the "pro-aging factors" that suppress neurogenesis--the formation of new brain cells in regions important for memory--which when introduced into younger animals can contribute to cognitive decline.

In a new study, published online on July 6, 2015 in Nature Medicine, Villeda and  Wyss-Coray followed up on these findings, as well as other studies correlating high B2M blood levels with cognitive dysfunction in Alzheimer's disease, HIV-associated dementia, and as a consequence of chronic dialysis for kidney disease.

The researchers observed that when B2M was administered to young mice, either via the circulatory system or directly into the brain, the mice performed poorly on tests of learning and memory compared to untreated mice, and neurogenesis was also suppressed in these mice.

These experiments were complemented by genetic manipulations in which some mice were engineered to lack a gene known as Tap1, which is crucial for the MHC I complex to make its way to the cell surface. In these mice, administration of B2M in young mice had no significant effect, either in tests of learning or in assessments of neurogenesis.

The group also bred mice missing the gene for B2M itself. These mice performed better than their normal counterparts on learning tests well into old age, and their brains did not exhibit the decline in neurogenesis typically seen in aged mice.

Villeda emphasized that the effects on learning observed in the B2M-administration experiments were reversible—30 days after the B2M injections, the treated mice performed as well on tests as untreated mice, indicating that B2M-induced cognitive decline in humans could potentially be treated with targeted drugs.

"From a translational perspective, we are interested in developing antibodies or small molecules to target this protein late in life," said Villeda. "Since B2M goes up with age in blood, cerebrospinal fluid (CSF), and also in the brain itself, this allows us multiple avenues in which to target this protein therapeutically."

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