Principal Investigator: Prof Jean van den Elsen

Lead institution: University of Bath

Award amount: £201,845 over 3 years

Prof Jean van den Elsen and team

Professor Jean van den Elsen (standing, right) with co-applicants Dr Rob Williams (standing, left), Dr Omar Kassar (seated). A third co-applicant, Professor Paul Francis of King’s College London, is not pictured.

Credit: AP Commercial Photography

Protein glycation in Alzheimer’s disease: implications for dementia diagnosis, prognosis and therapy

This grant was awarded in 2014 and the project has recently reported some interesting results, which have been published in the journal Scientific Reports.

In short:

  • For the first time a molecular “tipping point” has been demonstrated in Alzheimer’s, linking high blood sugar with this debilitating disease.
  • High levels of the blood sugar glucose damages a vital enzyme involved in inflammation response to the early stages of Alzheimer’s, via the process of glycation. 
  • Discovery will further understanding of Alzheimer’s progression and could help with earlier diagnosis and, eventually, treatments.

Abnormally high blood sugar levels, or hyperglycaemia, is well-known as a characteristic of diabetes and obesity, but its link to Alzheimer’s disease is less familiar.

Diabetes patients have an increased risk of developing Alzheimer’s disease compared to healthy individuals. In Alzheimer’s disease abnormal proteins aggregate to form plaques and tangles in the brain which progressively damage the brain and lead to severe cognitive decline.

The ability of glucose and its break-down products to damage proteins in cells via the process of glycation was already known, but the specific molecular link between glucose and Alzheimer’s was not understood.  Working with colleagues at the Wolfson Centre for Age Related Diseases, King’s College London, the team at the University of Bath have unravelled the link.

By studying brain samples from people with and without Alzheimer’s using a sensitive technique to detect glycation, the team discovered that in the early stages of Alzheimer’s, glycation damages an enzyme called macrophage migration inhibitory factor (MIF) which plays a role in immune response and insulin regulation.

MIF is involved in the response of brain cells called glia to the build-up of abnormal proteins in the brain during Alzheimer’s disease, and the researchers believe that inhibition and reduction of MIF activity caused by glycation could be the ‘tipping point’ in disease progression. It appears that as Alzheimer’s progresses, glycation of these enzymes increases.

Professor Jean van den Elsen, from the University of Bath Department of Biology and Biochemistry, said:  “We’ve shown that this enzyme is already modified by glucose in the brains of individuals at the early stages of Alzheimer’s disease.  We are now investigating if we can detect similar changes in blood.  Normally MIF would be part of the immune response to the build-up of abnormal proteins in the brain, and we think that because sugar damage reduces some MIF functions and completely inhibits others that this could be a tipping point that allows Alzheimer’s to develop”.

Dr Rob Williams, also from the Department of Biology and Biochemistry, added: “Knowing this will be vital to developing a chronology of how Alzheimer’s progresses and we hope will help us identify those at risk of Alzheimer’s and lead to new treatments or ways to prevent the disease.”

Dr Omar Kassaar, from the University of Bath, added: “Excess sugar is well known to be bad for us when it comes to diabetes and obesity, but this potential link with Alzheimer’s disease is yet another reason that we should be controlling our sugar intake in our diets.”

 

Human brain tissue for this study was provided through Brains for Dementia, a joint initiative between Alzheimer’s Society and Alzheimer’s Research UK in association with the Medical Research Council.