Serafini, Sara (2025) Advances in Alzheimer's Disease Research: From Plasma Signatures to Fyn Tyrosine Kinase Inhibition Strategies. [Tesi di dottorato]

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Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by cognitive decline, memory loss, and impaired daily functioning. Despite extensive research efforts, the aetiology of AD remains unclear, and no effective disease-modifying treatments are currently available. This thesis aimed to identify novel potential stratification strategies for AD patients to determine clinical subtypes that could potentially benefit from treatment with Fyn tyrosine kinase inhibitors (TKIs). A multidisciplinary approach integrating clinical investigations, plasma metabolomic analysis, and cellular and molecular studies was employed. The study identified potential blood signatures, including elevated levels of tumour necrosis factor-alpha (TNFα) in the early stages of AD, such as in patients with subjective cognitive impairment (SCI). Altered profiles of certain phosphatidylcholines, particularly Lysophosphatidylcholines (Lyso-PC) C26:1 and C28:1, were observed in AD patients with elevated levels of TNFα and beta-amyloid 42 (Aβ42). Moreover, in a subset of patients presenting with increased Lyso-PC, TNFα, and Aβ42 levels, peripheral blood mononuclear cells exhibited heightened phosphorylation of amyloid precursor protein at Tyr682 (APPpTyr682) and increased activation of Fyn. Notably, APPpTyr682 and Fyn activation have been previously linked to the accumulation of Aβ42 in the neurons of AD patients, suggesting a potential mechanistic link between these biomarkers and disease progression. This research proposes a novel approach to stratifying AD patients, potentially paving the way for more targeted treatments using Fyn TK inhibitors. The identification of specific blood biomarkers and cellular changes associated with disease progression could lead to improved early diagnosis and personalized therapeutic strategies. These findings may significantly impact our understanding of AD mechanisms and contribute to the development of more effective interventions in the future. Furthermore, a six-month research placement at Angelini Pharma was conducted to investigate strategies for enhancing blood-brain barrier (BBB) permeability of Fyn TKIs. This experience facilitated a comprehensive analysis of potential strategies, identifying nanoparticle formulations for intranasal administration as a viable therapeutic approach.

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