All four of the PhD students in the ageing brain research group of the CEXS-UPF studied biology at the UPF. “It is our direct source of students!”, says Paco Muñoz López, head of the group and professor at that university. A postdoctoral researcher completes the group, which focuses on nitro-oxidative stress and its link to Alzheimer’s disease.
“The most important risk factor in Alzheimer’s disease is age –says Muñoz–. About 10% of the population over 65 suffer Alzheimer’s, but the percentage goes up to 50% in over 80 year-olds. I think it’s just the price to pay for a life of thinking, a consequence of the overuse of our neurones”. There are also genetic factors, but less than 3% of the cases are familial, mostly due to mutations in APP (amyloid precursor protein) and presenilins.
An aggregation problem
At a molecular level, Alzheimer’s is triggered by the accumulation of amyloid ß-peptide (Aß) aggregates in the brain, in particular in the hippocampus and the cortex. The Aß is a subproduct of the processing of APP, a ubiquitous protein of unknown function. Muñoz’s group suggests that it is a key protein in memory and learning processes.
In other parts of the body, the soluble Aß is eliminated through the liver, but in the case of the brain it cannot pass the bloodbrain barrier and therefore it accumulates. “Once it aggregates the problem starts”, says Muñoz. The group tries to understand how and when APP is processed by BACE1, the enzyme that generates Aß from APP, as well as the role of nitroxidative stress in BACE1 activation and Aß neurotoxicity. When the Aß aggregates it produces free radicals which react with the neuronal nitric oxide, generating peroxynitrite, a very reactive anion that harms proteins.
On the other hand, Aß oligomers bind different membrane proteins, in particular NMDA, a huge receptor for glutamate that, when opened, lets Ca2+ into the cell. When Aß amyloid binds NMDA, it forces the receptor to be half open all the time. This allows a constant flux of Ca2+ into the neurone which, slowly, kills it. The inhibition of the NMDA receptor has been proposed as a specific treatment to slow down Alzheimer’s. But there are other proteins that could pave the way to new therapeutic targets.
One of these was pinpointed by Muñoz’s group in a study that took them four years. “We added Aß to cell cultures and then did some proteomic analyses to determine which proteins had been nitrated. One of them was TPI, a key glycolytic enzyme. Interestingly, glucose consumption in the neurones of people with Alzheimer’s is lower than normal, and it wasn’t known why”, explains the biologist. They looked in APP and presenilin transgenic mice and in brains of Alzheimer’s patients. In both cases they saw that TPI was nitrated. The biochemical studies that followed and some computational studies done by colleagues at the GRIB (UPF-IMIM) confirmed that, when nitrated, TPI was less active. A three-month stay in Japan followed, where Muñoz cloned the TPI enzyme. Finally, they were able to show by electron microscopy that the nitrated TPI aggregated within the cell.
“So far we have focused on the pathological role of APP. But in the near future I want to understand the physiological role of APP in memory, something that remains a mystery”, concludes Muñoz.
This article was published in the El·lipse publication