ISS, Key Alzheimer’s Mechanism Discovered, Hope for Diagnosis and Treatment

Italian research takes a step forward in the fight against Alzheimer’s, opening up new possibilities for early diagnosis and treatment. Scientists from the Istituto Superiore di Sanità, the IRCCS San Raffaele in Rome and the National Research Council have revealed a new molecular mechanism underlying the loss of memory and cognitive abilities that characterize dementia. At the center of the discovery is a protein that inside neurons has the task of repairing damage to DNA. The study, published in ‘Embo Reports’ – the ISS reports – adds important new pieces of knowledge in a pathology that affects about 2 million people in Italy (1.1 million with dementia and 900 thousand with a mild cognitive disorder), and in the future could provide a new biomarker of the disease. For a test capable of intercepting it earlier.

The research – reports the ISS – demonstrates for the first time that the enzyme Dna-PKcs, a protein kinase involved in DNA repair mechanisms inside nerve cells, is located in synapses, that is, in the functional contact point at which the transmission of information between neurons occurs. The authors observed that in synapses Dna-PKcs is responsible for the phosphorylation (a particular modification of the structure of a molecule) of PSD-95, a protein responsible for the organization of synapses, their structure and consequently also the transmission of signals. “The modification of PSD-95 by Dna-PKcs makes PSD-95 stable inside synapses and not susceptible to degradation, as occurs for example in Alzheimer’s”, explains Daniela Merlo, research director of the Department of Neuroscience and director of the Interdepartmental Structure on Dementia of the ISS, coordinator of the study.

In 2016, the same group of scientists discovered that the activity of the Dna-PKcs enzyme is inhibited by beta-amyloid, the protein that typically accumulates in the brains of patients with Alzheimer’s. In the brains of patients, in fact, a decrease in the levels and activity of Dna-PKcs was observed. And the failure to repair DNA damage that results from the inhibition of Dna-PKcs is implicated in the death of neurons observed in several neurodegenerative diseases, including Alzheimer’s. “This new discovery demonstrates that Dna-PKcs plays a fundamental role in memory and cognitive deficits that characterize Alzheimer’s and dementias”, underline Cristiana Mollinari, researcher at the Institute of Translational Pharmacology of the CNR, and Leonardo Lupacchini, researcher at San Raffaele Rome, first authors of the article. “Therefore – Merlo highlights – 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 the synapses due to its lack of phosphorylation, and consequently the dysfunction of the synapses. Which is at the basis of memory loss”.

“The lack of PSD-95 phosphorylation in neurodegenerative diseases characterized by cognitive deficit could represent a new biomarker for early diagnosis and monitoring of the disease over time”, Merlo proposes.

“This study – comments Enrico Garaci, president of the Technical Scientific Committee of the IRCCS San Raffaele Rome – has identified new cellular pathways that can be modulated pharmacologically, and therefore therapeutic strategies aimed at regulating the activity of DNA-PKcs and the integrity of PSD-95 could have an important therapeutic impact on the loss of synapses and therefore on cognitive deficits in various neurological diseases”.

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“Alzheimer’s disease and dementias have a considerable impact in terms of social and health care and represent one of the major causes of disability in the general population and in the elderly in particular, representing one of the most relevant problems in terms of public health”, says Massimo Fini, scientific director of the IRCCS San Raffaele Roma.