An integrated biotechnological approach to intercept early toxic drivers of Parkinsons and Alzheimers Disease

Protein aggregation is a central driver of neurodegeneration. In disease, proteins such as a-synuclein (aSyn), Abeta, and Tau initially misfold and assemble into beta-sheetrich oligomers and protofibrils that arise long before clinical symptoms. These early toxic species disrupt cellular homeostasis, seed downstream fibrillization, and ultimately drive neuronal failure. In ProTecT, we intend to deploy cutting-edge biotechnological strategies to target these earliest molecular triggers of disease. In Parkinsons disease (PD), aggregation of aSyn plays a causal role in the progressive loss of dopaminergic neurons in the substantia nigra, leading to motor impairment and, later, cognitive and emotional decline. Increasing evidence points to aSyn oligomers, rather than mature fibrils, as the main neurotoxic entities. However, their transient and heterogeneous nature has long hindered drug development. Through a computational modelling pipeline, we identified a neuropeptide that binds aSyn oligomers with nanomolar affinity, blocks fibrillization, and provides strong neuroprotection in a PD model animal following intranasal delivery. We intend to advance this peptide toward translationtogether with additional top-ranked candidates thereby establishing a new modality to neutralize the earliest toxic aSyn species. Our structural studies further uncovered an oligomer-specific epitope in the N-terminal region of aSyn, enabling complementary approaches. AIengineered human monoclonal antibodies directed against this epitope exhibit striking oligomer selectivity and unreported aggregation inhibitory potential. Using the same structural insight, we developed a virus-like particle (VLP) vaccine that displays this epitope in its pathogenic conformation, eliciting durable, highly selective immune responses. ProTecT aims to refine further and validate the therapeutic potential of these next-generation immunotherapies. Because early PD pathology may originate in the gut, we also intend to develop engineered probiotics that secrete computationally designed anti- oligomer nanobodies, creating a living therapeutic platform capable of neutralizing aSyn toxic species before they reach the central nervous system. In Alzheimers disease (AD), the interplay between aggregated Abeta and Tau underlies early synaptic dysfunction and the progressive loss of neurons in the hippocampus and associative cortical regions that mediate learning and memory. Pathogenic forms of Abeta and Tau exhibit disease-specific post- translational modifications (PTM) that promote oligomerization, seeding, and neuroinflammation. Leveraging the same biotechnology framework as in PD, we designed a multivalent VLP vaccine displaying PTM-defined Abeta and Tau epitopes unique to toxic assemblies. By recreating these molecular signatures on a modular scaffold, we aim to elicit coordinated and selective immune responses against early toxic assemblies in AD. Together, these peptide inhibitors, AI-designed antibodies/nanobodies, nanotechnological vaccines, and microbiome-engineered delivery systems form a coherent biotechnology programme targeting early toxic aggregates at their point of origin. By addressing the earliest molecular drivers of PD and AD, the project establishes a mechanistically grounded and technologically advanced path toward truly disease-modifying interventions.