New methods to investigate the viral-like trans-synaptic transmission mechanism of Alzheimer’s Disease

Diplôme Master New methods to investigate the viral-like trans-synaptic transmission mechanism of Alzheimer’s Disease eng 2025-04-15 author Broisin Lisa Angèle Claire 0009-0000-8204-9278 407564 Unité d'anatomie (ANATOMIE) Lisa Broisin director Lamy Christophe 918803 Unité d'anatomie (ANATOMIE) author Jorda Siquier Tomas 952752 Unité d'anatomie (ANATOMIE) Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the progressive spread of pathological proteins throughout the brain in a stereotypical manner, following specific neuronal networks. Recent work suggests that pathological proteins may spread via vesicular viral-like trans-synaptic transmission. While this mechanism has been studied in preclinical models, it has never been directly investigated in the human brain. This study aims at developing and optimizing new methods to explore the vesicular viral-like transsynaptic transmission of AD patients using postmortem brain samples from the Geneva Brain Bank (GBB). We successfully implemented a 4x Expansion Microscopy (ExM) protocol on formalin-fixed paraffin-embedded (FFPE) brain sections, achieving uniform tissue expansion while preserving structural integrity, including samples stored since 1998, thus enabling high-resolution imaging of synaptic markers. In parallel, an RNA extraction protocol was optimized for FFPE tissues by extending lysis and final elution incubations times and introducing a chemical cross-link reversal step, which significantly improved RNA yield. Notably, RNA extraction yielded satisfactory results even from samples preserved for over a decade. Importantly, we demonstrated for the first time the feasibility of performing RNA sequencing (RNA-seq) on FFPE brain samples from the GBB. Together, these new tools will actively contribute to advancing the molecular and histological characterization of AD pathology in human tissues, promoting human-based investigations and opening new perspectives for translational research in AD, thereby strengthening future translational studies in the field. Alzheimer’s disease (AD) Neurodegenerative disorder Pathological proteins Translational research Expansion Microscopy (ExM) RNA extraction RNA sequencing (RNA-seq) Formalin-fixed paraffin-embedded (FFPE) Postmortem brain samples Geneva Brain Bank (GBB) Trans-synaptic transmission Dewey 610 Dewey 616.8 Maîtrise universitaire interdisciplinaire en neurosciences 3 Faculté de médecine 2 16 Centre interfacultaire de neurosciences 0D9 false 561d9e8b-e50d-4864-b07f-e138118eb63f Master thesis Restricted Master_thesis_Lisa_Broisin.pdf 19370986 application/pdf Private 2027-07-01 59b70301c9f8e29088985260abd1745031cdcc5e82e78f11bf4cbe74bd335dab embargoedAccess Faculté de médecine Centres et instituts / Centre interfacultaire de neurosciences

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