Brain connectivity and complexity parameters to monitor disease progression in dementia patients and anti-inflammatory nanotherapeutics in a preclinical model of AD

Alzheimer's Disease (AD) is multifactorial disorder where the non-linear interaction between genetic, biological andenvironmental factors accounts for interindividual clinical variability. The lack of an effective cure and the preclinical data onanimal models, made it clear that, once neurodegeneration is too advanced, treatments have limited effects. Early treatmentsrequire new reliable tests to identify the initial manifestations of the disease. Since early diagnosis might increase theeffectiveness of therapeutic interventions, our study will focus on the identification of early biomarkers of AD. The impairmentof functional cortical connectivity can be detected in early and prodromal AD through neurophysiological assessment andEEG measurements. In this study we will investigate complex cortical connectivity networks, which are already deterioratedin early AD, as a reliable marker of cognitive progression. Our goal is to identify neurophysiological indices and life-stylefactors to characterize early AD and mild cognitive impairment (MCI). MCI is characterized by measurable cognitive deficit,but not overt dementia. Half of the MCI patients progresses to or, more accurately, is already in a prodromal form of AD. Theexpected results of this project will potentially offer a new test to discriminate with accuracy the cases of MCI due to AD.These patients would be the ideal candidate to undergo early interventions.Concurrently, the study of AD onset and progression in a mouse model, will allow to evaluate the causal effect ofinflammation on the disease phenotype and to develop a new class of biomimetic nanoparticles (the leukosomes) able totarget and overcome the blood brain barrier to resolve neuroinflammation. In AD, the chronic activation of M1 microgliatriggers the release of pro-inflammatory cytokines and chemokines, which can lead to further neurodegeneration. Inhibition ofmicroglia over-activation and neuroinflammation could represent a promising strategy for the treatment of AD. Unfortunately,targeting brain inflammation through a systemic pharmacological approach does not hold ground clinically, because of poordelivery across the blood brain barrier. We will develop next-generation targeted therapies based on the specific action ofbiomimetic anti-inflammatory nanoparticles at the site of brain damage. We hypothesize that the selective neutralization ordownregulation of the pathogenic and pro-inflammatory signaling, will significantly improve the therapeutic outcome andinhibit or slow down the progression of AD.The project will be divided in the following three specific aims:- Specific Aim 1: To characterize AD and MCI subjects performing clinical, psycho-cognitive, metabolic, physical functioningand different neurophysiological investigations, to identify standardized multidimensional biomarkers of AD. These data willbe compared between patients and a group of age- sex- and education-matched healthy subjects.- Specific Aim 2: To characterize changes in brain connectivity and complexity in a sporadic AD-like mouse model and tocorrelate the neurophysiological indices to AD hallmarks and neuroinflammation.- Specific Aim 3: To evaluate the effect of anti-inflammatory biomimetic nanoparticles to target neuroinflammation in ADmouse model and to ameliorate AD phenotype.