• Alzheimer

Interferon type-1 dependent innate immune response (IFN-IIR) is a physiological pathway commonly exploited by our organism to “interfere” with the invasion of pathogens, mainly viruses. Through the combined action of INF alpha and beta this process obstacle viral replication by the induction of different pathways which eventually converge in the degradation of the infected cells and the promotion of inflammatory response in non-infected cells.
As the immune response itself, though, INF-IIR represents a double-edged sword for our system, since its dysregulation appears to be implied in the etiology of many pathologic conditions (autoimmune diseases, chronic and acute inflammation, …). It is known, in fact, that the mediators of innate response act in an aspecific way which means they indiscriminately act against exogenous and endogenous components, so they can be self-reactive.
The aim of this thesis is to evaluate the role of INF-1- mediated response in the pathophysiology of two degenerative conditions: myotonic dystrophy type 1 (MD1) and Alzheimer’s disease (AD).
Myotonic dystrophy type 1 is an autosomal dominant multisystem disease due to CTG repeats expansion in the DMPK gene on chromosome 19. RNAs containing CUG repeats accumulate in the nuclei of DM1 myoblasts (foci) and they can give rise to dsRNA structures (the result of the transcription of the mutant DMPK) which elicit IFN type 1 (IFN1) production. Interferon response could inhibit muscle differentiation. We investigated the inflammatory process utilizing two DM myoblasts: A3 (DM1 patient) and A7 (healthy control). We compared the RT-PCR results for the 2’-5’-Oligo Adenylate Synthetase 1 (2’-5’-OAS1) and GUS-beta (housekeeping gene). Our preliminary results showed that OAS1 progressively increases in A3, while it isn’t altered in A7 over time. Moreover, Transmission Electron Microscope (TEM) analysis showed an increase in RER stress for A3 over differentiation and not in the formation of autophagic vacuoli. These insights seem to evaluate the hypothesis that the myogenesis inhibition typical of DM1 patients may be linked to INF1 activation rather than to increased autophagy.
In the second part of our study, we investigated the role of innate immune response on Alzheimer’s disease (AD) patients. AD is the predominant cause of dementia among aged people and it is characterized by extracellular deposition of amyloid-beta (A-beta) and intraneuronal accumulation of neurofibrillary tangles (NFTs). Extracellular A-beta aggregations seem to stimulate innate immunity and induce the production of inflammatory mediators (NO, ROS, cytokines) and this could be the cause of the neuroinflammatory process responsible for neurodegeneration, the hallmark of AD condition. Since A-beta production may not be the cause but an effect of the disease, in our study we wanted to investigate other possible upstream causes.
Growing evidence suggests that there is a crosstalk between the immune system and the central nervous system. For this reason, lymphocytes and neutrophils may represent useful sentinels of the inflammatory activation displayed into the CNS. From preliminary TEM results, in a comparison between lymphocytes from patients and healthy controls, we can observe a pronounced formation of autophagic vacuoli related to the gravity of the patients. These hints induce us to perform RT-PCR analysis to investigate whether there is an implemented OAS1 expression in patients versus controls, as observed for DM1, in order to evaluate the potential involvement of INF-IIR in the pathologic phenotype.
The use of peripheral blood biomarkers would be a useful tool for the diagnosis of disease before neurons undergo complete degeneration. Moreover, we intend to carry out parallel analyses through Raman spectroscopy over sera samples (DAT vs CTR). In addition, we are setting ourselves the target to test neuron-derived exosomes (NDEs) given that they represent an innovative carrier of information about the general status of our organism and, specifically, about the CNS.
These goals could be performed with considerable advantages since the collection of blood withdrawals is not invasive and elucidations on the pathophysiology of these diseases could predict the risk of disease with effective advance and properly orientate therapeutic strategies.