Denise Grana

CURRICULUM

Born in Codogno (LO) the 27th of March 1990, I earned my Bachelor’s degree in Biological Sciences at the University of Milan-Bicocca and my Master’s degree in Neurobiology at the University of Pavia, after a thesis’ internship in the field of Amyotrophic Lateral Sclerosis. Interested in neurosciences, in December 2014 I enrolled in a PhD course at the University of Milan-Bicocca, in Prof. Carlo Ferrarese’s laboratory, working on neuroinflammation in Alzheimer’s Disease. In March 2017 I joined Prof. Michael T. Heneka’s group, at the University of Bonn Medical Center, Germany, where I spent the last period of my doctoral programme.

RESEARCH PROJECT

Behavioural and psychological symptoms of dementia: role of the immune response

  • Track: Experimental Neuroscience
  • Tutor: Lucio Tremolizzo
  • Co-tutor: Elisa Conti
  • Supervisor (during external stage): prof. Michael t. Heneka

Behavioural and Psychological Symptoms of Dementia (BPSD) have a high incidence in Alzheimer’s Disease (AD) and represent a huge additional problem for caregivers in patients’ management. Thus, the additional help of qualified staff is frequently needed, leading to patients’ premature institutionalization and, therefore, increasing the costs of healthcare. Even though the causes of these anomalies have not been clarified yet, several studies hypothesized the involvement of the immune system. For example, systemic inflammatory states have been demonstrated to influence BPSD-like manifestations in sepsis mouse models and, similarly, delirium clinical condition suggested the contribution of peripheral immune responses in the genesis of behavioural disturbances. In light of these evidences, the TSPO/DBI system seems an interesting target to investigate. Indeed, it is expressed in CNS, where it is upregulated following neuroinflammation but it has also been identified in periphery and, here, it has been shown to be altered in different neuropsychiatric conditions. Moreover, it is responsible for the biosynthesis of neurosteroids, which have been demonstrated to be involved in mood control through their GABAA receptor modulatory action, and its activation pathway influences BDNF production, which is important for neuronal circuits. In addition, TSPO has displayed the ability to regulate monocytes chemotaxis and this process, together with neutrophils migration towards AD brain, is fundamental to sustain neuroinflammation.

Thus, the aim of this study was to examine the TSPO/DBI system in AD patients as well as in healthy controls, in order to identify possible alterations that could influence BPSD manifestations, with particular attention to agitation/aggression symptoms. Moreover, to verify the disease-specificity of these putative variations, we also analysed the same system in an MCI cohort and in a group of patients diagnosed with non-determined cognitive impairment (NDCI). Our interest was addressed not only to TSPO-dependent neurosteroidogenic pathway but also to TSPO-regulated monocytes migration. Moreover, we explored neutrophils infiltration in mouse models of AD (APP/PS1) as well as NLRP3-inflammasome deficiency superimposed on AD background (APP/PS1/Nlrp3-/-). Indeed, NLRP3 complex has been shown to be triggered by Neutrophils Extracellular Traps (NETs) that are released by activated neutrophils in brain parenchyma. Our results showed that TSPO endogenous ligand (DBI) is increased in serum of AD patients compared to controls, although there are no significant differences neither in TSPO nor in the products of its activation pathway between the two cohorts. However, dichotomizing AD subjects according to the absence or presence of agitation/aggression symptoms, the same parameters above-mentioned were almost identical in the two groups, suggesting that the TSPO/DBI system is not implicated in the onset of these disturbances. In addition, since we detected higher DBI serum levels in MCI as well as NDCI subjects compared to controls, we propose that this peptide more likely represents a marker of degeneration rather than AD pathology and this hypothesis is further supported by the correlation we found between DBI and t-tau in the CSF of AD patients. Also, given the correlation of serum DBI concentration to its CSF one, we speculated the existence of a relationship between these two compartments. On the other hand, we demonstrated that not only oligomeric Aβ influences monocytes chemotaxis but also that this process is much more stimulated in cells isolated from AD patients than in the ones from controls. Lastly, we confirmed that neutrophils infiltrate the brains of APP/PS1 as well as APP/PS1/Nlrp3-/- mice and that they release toxic NETs in the parenchyma. Moreover, this infiltration was more evident in LPS-treated animals, suggesting a role for peripheral inflammatory processes in boosting central neuroinflammation.

ABROAD STAGE

03/15/2017 – 11/30/2017: at the Universitätsklinikum in Bonn (Germany), in the Laboratory of Clinical Neuroscience run by Prof. Michael T. Heneka

RECENT PUBLICATIONS AND CONGRESSES

Publications

Congresses

  • Tremolizzo L, Grana D, Conti E, Stefanoni G, Zoia CP, Bossi M, Aliprandi A, Appollonio I, Ferrarese C. Beta-amyloid induces peripheral chemotactic response: a preliminary study. (XXII National Congress SINdem. Florence, Italy. March 16-18, 2017).
  • Conti E, Tremolizzo L, Grana D, Zoia CP, Arosio A, Cereda D, Stefanoni G, Villa C, Combi R, Aliprandi A, Salmaggi A, Appollonio I, Ferrarese C. Interaction between cholinergic, immune and inflammatory systems in Alzheimer’s disease: the IMMUNAD project. (XXII National Congress SINdem. Florence, Italy. March 16-18, 2017).
  • Grana D, Conti E, Zoia CP, Maggioni L, Arosio A, Stefanoni G, Aliprandi A, Appollonio I, Ferrarese C, Tremolizzo L. Behavioural anomalies in neurodegenerative diseases: role of the immune response. JAD, 2016; 53: S33. (Second International Meeting of the Milan Center for Neuroscience (NeuroMi). Milan, Italy. July 06-08, 2016).
  • Grana D, Conti E, Zoia CP, Maggioni L, Arosio A, Stefanoni G, Aliprandi A, Appollonio I, Ferrarese C, Tremolizzo L. Behavioural anomalies in neurodegenerative diseases: role of the immune response. (Second European Meeting of Neuroscience by PhD students. Grenoble, France. April 29, 2016).

FURTHER INFO

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Elisabetta Donzelli
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