A proteomic approach to unravel neurodegeneration
TL;DR
The potential of proteomics to characterize the molecular complexity of AD and reveal interconnected changes across different levels of disease biology is demonstrated, supporting a view of AD as a progressive disruption of cellular and intercellular communication and emphasizing the need for multi-targeted approaches to understand and treat the disease.
Abstract
Alzheimer’s disease (AD) is a progressive and complex neurodegenerative disorder characterized by amyloid-β (Aβ) plaques and hyperphosphorylated tau, accompanied by changes in synaptic function, metabolism, proteostasis, neuroinflammation, glial activity, and extracellular signaling. The interaction between these processes contributes to the molecular heterogeneity observed between individuals, disease stages, and clinical subtypes. In this thesis, I used proteomics as a central approach to investigate AD from complementary perspectives, including disease heterogeneity, extracellular vesicle (EV) signaling, therapeutic intervention, and I developed an accessible proteomics workflow. I first investigated molecular differences between early-onset familial AD (EOAD) and late-onset AD (LOAD) using 115 human post-mortem brain tissues. EOAD showed stronger dysregulation of mitochondrial oxidative phosphorylation and synaptic pathways, while peptide-level analysis identified phosphorylated tau isoforms as candidate subtype- and stage-specific biomarkers. In addition, Aβ positivity in cognitively normal individuals was compatible with both preclinical AD and resilience, highlighting a biologically active prodromal phase. I next investigated the relationship between extracellular matrix remodeling and EV composition in the APP/PSEN1 mouse model. In the 5xFAD model, treatment with the neurotrophin mimetic BNN27 altered proteins and pathways related to Aβ metabolism, synaptic function, and neuroinflammation, accompanied by reduced amyloid plaque burden, increased hippocampal neurogenesis, and improved memory performance. Finally, I developed a cost-effective and reproducible sTRAP workflow that improved protein and peptide identification from low-input samples and captured disease-relevant proteomic signatures in 5xFAD hippocampal tissue. Altogether, these findings demonstrate the potential of proteomics to characterize the molecular complexity of AD and reveal interconnected changes across different levels of disease biology. They further support a view of AD as a progressive disruption of cellular and intercellular communication, emphasizing the need for multi-targeted approaches to understand and treat the disease.