Immune system molecule promotes cognitive decline; could lead to dementia cure
Researchers have revealed that an immune system molecule dubbed beta-2 microglobulin, or B2M, is responsible for blocking regeneration of brain cells and promotion of cognitive decline and are hopeful that it may lead to cure for dementia and other similar diseases.
The study by researchers at University of California, San Francisco and Stanford School of Medicine, published in Nature Medicine, reveals that B2M is a component of a larger molecule called MHC I (major histocompatibility complex class I), which plays a major role in the adaptive immune system.
Researchers have shown that the B2M-MHC I complex, which is present in all cells in the body except red blood cells and plasma cells, could be affecting the brain in ways which are obviously not related to immunity—guiding brain development, and hence could be affecting nerve cell communication as well as affecting behavior in humans.
Though researchers are yet to fully understand that exact mechanism by which B2M works, Saul A. Villeda, PhD, a UCSF Faculty Fellow and co-senior author of the new study said that they are looking at the ‘traditional’ immune contribution to effects on cognition, and what is the non-traditional neural contribution as B2M increases with age, both in the blood and in the brain.
In a previous research, Villeda and Tony Wyss-Coray, PhD, professor of neurology at Stanford, showed that if circulatory system of a young mouse is connected to that of an old mouse, there is a reversal of decline in learning ability that typically emerge as mice age. Further, the duo then showed that blood from older animals appears to contain “pro-aging factors” that suppress neurogenesis—the sprouting of new brain cells in regions important for memory—which in turn can contribute to cognitive decline.
Villeda and co-senior author Wyss-Coray joined forces for their latest research to carry out studies to correlate 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 showed that B2M levels steadily rise with age in mice, and are also higher in young mice in which the circulatory system is joined to that of an older mouse. These findings were confirmed in humans, in whom B2M levels rose with age in both blood and in the cerebrospinal fluid (CSF) that bathes the brain.
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, CSF, and also in the brain itself, this allows us multiple avenues in which to target this protein therapeutically.”