Scientists from Sanford Burnham Prebys Medical Discovery Institute (SBP) have discovered a mechanism that may protect the cognitive function of older mice as well as human aging models.

The findings published in the Proceedings of the National Academy of Sciences in advance of print suggest that AXL is activated in the brain in order to protect neurons in the brain from damage during aging as well as in a preliminary mouse model of neurodegenerative diseases.

We speculate that activation of this AXL mechanism may contribute to cognitive performance during aging which spurs further cognitive performance and is a hallmark of senescence-the bodys inability to physically live a normal lifespan said Michael Rapoport MD assistant professor in the Matthias Heisenberg department of neurology at SBP. Vascular integrity frequency and volume loss related to cognitive impairment are persistent however and patients with dementia could represent a different population. With our study in mice we found that activation of this protein in the frontal cortex of the brain represents a potential new therapeutic target protecting oligodendrocytes from damage.

Epigenetic modulation of oligodendrocyte density and frequency.

Oligodendrocytes are the most abundant brain cells in mammals where they support brain cells energy consumption. It was previously hypothesized based on animal models that all oligodendrocytes lack a specific protein called Mller filopontine 3 (Mf3) altogether and therefore their total number and density in the brain is fixed. However Rapoport and his colleagues found that increasing Mf3 would alter levels of two other proteins that are overexpressed in oligodendrocytes. One of these proteins is the molecule Uhral a well-known blood-clotting protein. Uhral was recruited to the brain for expression in a growing but in vitro rodent model increased concentrations of Uhral led to significantly lower levels of Mf3 than those experienced in normal mice.

We investigated the downstream effects of increasing Mf3 overexpression in oligodendrocytes. Decreased-expression of Mf3 was associated with increased severity of memory deficits as well as a broad association between systemic Mf3 protein overexpression and age-related cognitive impairment.

Michael Rapoport MD assistant professor in the Matthias Heisenberg department of neurology at SBP.

To test whether Mf3s ability to protect oligodendrocytes prevented cognitive impairment the researchers raised naive oligodendrocytes to overexpress Mf3 in a mouse model without the ability to modulate other critical processes in the brain. In the treatment group approximately 30 percent of the animals number of oligodendrocytes were overexpressed-compared to 7-9 percent in the control group.

To our surprise overexpression of Mf3 was associated with decreased brain cortical thickness and cognitive performance in a number of worm and fruit flies of the age range from one to 72 weeks in comparison to control flies Rapoport said. And our results showed that increased Mf3 expression perhaps also observed impact on brain glucose metabolism and glycolytic function via activation of the cofactors 2A and 4B.