A protein has been discovered that causes fatty food to destroy the brain

Fatty food doesn't just affect your figure: in mice, it sharply reduces levels of the PQBP1 protein in the cerebral cortex, destroying connections between neurons and undermining memory. The molecular mechanism behind this process was uncovered by Hitoshi Okazawa's team at the Tokyo University of Science in collaboration with colleagues from Teikyo University. The results of the study were published in the journal Molecular Psychiatry.

It has long been known that high-calorie diets lead to obesity and diabetes. Accumulated evidence also points to a serious blow to the brain — from declining cognitive abilities to an increased risk of neurodegeneration, including Alzheimer's disease. Among the likely causes, scientists have cited brain inflammation and insulin resistance, but exactly what breakdown occurs inside neurons remained a mystery.

The key link turned out to be the protein PQBP1. It controls alternative splicing — the "recutting" of instructions read from DNA that allows a single gene to produce several protein variants at once. In mice on a high-fat diet, PQBP1 levels in the cortex dropped sharply: fatty food, through insulin signaling, suppressed the PPARgamma protein responsible for activating this gene. RNA sequencing showed that in rodents kept on such a diet for one and six weeks, the splicing disruption affected the very same synaptic genes as in mice from which PQBP1 had been preemptively deleted from neurons. The result was damaged synapses and failures in memory tests.

However, the damaged brain, as the authors note, is amenable to recovery. Pioglitazone — a drug long used for diabetes — restored the protein to normal levels, corrected the splicing of key genes, and improved memory in the experimental animals. Gene therapy also proved effective: a viral vector delivered a working copy of the needed gene to neurons, and even targeted restoration of individual target genes helped.

"Understanding how diet-related changes in PQBP1 affect splicing and synaptic function opens a new direction in developing treatments for cognitive impairments," says Okazawa.

All results so far have been obtained in mice, and new treatment approaches for the human brain are still a long way off. Nevertheless, the idea itself looks promising: an old diabetes drug may one day be able to protect memory in people at risk, and PQBP1-dependent splicing could become a target for fundamentally new medications. The authors intend to continue researching exactly how food reprograms our brain.