Alzheimer's, new protein identified as involved in memory loss

An Italian study by the Istituto Superiore di Sanità (Iss), Irccs San Raffaele Roma and the CNR adds a new piece to the understanding of Alzheimer's disease, opening up new possibilities for early diagnosis and treatment. Scientists have in fact unveiled a new molecular mechanism underlying the loss of memory and cognitive capacity that characterises dementia. At the heart of the discovery, published in 'Embo Reports', is a protein that within neurons has the task of repairing damage to the DNA.

The research - reports the Iss - shows for the first time that the enzyme Dna-PKcs - a protein kinase involved in DNA repair mechanisms within nerve cells - is located in the synapse, i.e. at the functional contact point where the transmission of information between neurons takes place. Here, Dna-PKcs is responsible for the phosphorylation (a particular modification of the structure of a molecule) of a protein (Psd-95) involved in the organisation of synapses, their structure and consequently also in the transmission of signals.

Already in 2016, the same group of scientists had discovered that the activity of the enzyme Dna-PKcs is inhibited by beta-amyloid, the protein that accumulates in the brains of Alzheimer's sufferers. Decreased levels and activity of Dna-PKcs were observed in the brains of sufferers. And the failure to repair DNA damage resulting from Dna-PKcs inhibition is implicated in the neuron death observed in several neurodegenerative diseases, including Alzheimer's.

"This new discovery shows that Dna-PKcs plays a key role in the memory and cognitive deficits that characterise Alzheimer's and dementia," explain Cristiana Mollinari researcher at the Institute of Translational Pharmacology (CNR) and Leonardo Lupacchini researcher at San Raffaele Rome, first authors of the article.

"The modification of Psd-95 by Dna-PKcs makes the former stable within synapses and not susceptible to degradation, as occurs in Alzheimer's disease," explains study co-ordinator Daniela Merlo, research director of the Department of Neuroscience and director of the Interdepartmental Structure on Dementia at the Iss, "Therefore this study proposes a new scenario in which in Alzheimer's disease but not only, the reduced enzymatic activity of Dna-PKcs, mediated by the accumulation of beta-amyloid, causes the reduction of Psd-95 levels in synapses due to its lack of phosphorylation, and consequently synapse dysfunction. Which underlies memory loss'.