’the proposal is set to investigate the role of patholo specilic T-cells as an
early prognostic marker for Alzheimer's disease (AD). AD is a progressive neurodegenerative disorder characterized by cognitive declino and the abgrrant accumulation of amyloid-§ (A§) and hyperphosphorylated tau protein (p-tau). Despite its important clinical implications, earlyand accurate diagnosis remains challenging, There is, indeed, great interest in the prognostic utilityof peripheral biomarkers as predictors of the future development of AD in individuale with early signs of cognitive decline, Mild cognitive impairinent (MO) is a critical prodromal phase of AD that offers a window of opportunity for intervention. Early and reliable identificatioo of individuals at high risk of conversion is therefore cnicial. Eyidence from our team indicates that AD patients specifically display small subsets of peiipheral A§-sensitive specific T-cells, characterized bythe elevated expression of phosphoiylated-PKC-delta or -zeta PMID: 22330173]. Furthermore, activated HLA-DR positive CD4(+) and CD8(+) T-cells were slightly and significantlyincreased in the peripheral blood of MO and earlyAD patients, respectively, when compared with healthyelderly controls but not in patients with other dementias [PMID: 2527Z040], suggesting a pathology specific T cell signature, In our proposal, T-cells collected from a cohort of MO subjects will be challenged with antigens associated with AD pathogenesis (i.e.: A§) and assayed for cytokine ptoduction and the expression of markers of activation byan established multiparameter flow cytometrypanel (REFs). The 1-year follow-up will associate person-specific T-cell response signatures with disease progression, with an expected 10-15% of MO subjecu converting to AD.
The diverse and complementaryexpertise of the applicant Teamis instiumental
for the successful development of the proposal as it combiiies &cade-long expertise in the investigation of the molecular determinants of AD (Dr. Granzotto; PI) with state-of-the-art skills in flow cytomeuyfor diagnostics (Dr. De Bellis: Co-PI).