Panzi, Chiara;
(2025)
Modulation of the spread of pathological
tau in vitro and in vivo.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Tau aggregates propagate through connected neuronal networks in tauopathies like Alzheimer’s disease. However, the mechanisms underlying this process are poorly understood. Different studies showed that tau release is dependent on neuronal activity and that pathological tau can be found in the extracellular space confined in extracellular vesicles or in a free form. A recent work demonstrated that modulation of metabotropic glutamate receptor activity and SNAP25 integrity influence the release of pathological tau from synaptosomes. To further explore this, I used botulinum neurotoxins (BoNTs) and tetanus neurotoxin (TeNT) as blocking agents to investigate their impact on tau release both in vitro and in vivo. BoNTs and TeNT enter synapses and cleave specific synaptic SNARE proteins, impairing vesicle fusion and neurotransmitter release. I aimed to demonstrate the potential of these neurotoxins, already widely used in clinics, in studying tauopathies and other neurodegenerative diseases. In primary hippocampal neurons overexpressing hTau and cultured in microfluidics chambers, I found that stimulation significantly increased the release of mutant (P301S) human tau (hTau) 1N4R, whereas treatment with BoNT type A (BoNT/A) effectively blocked it. The release of wild-type (WT) hTau was unaffected by these treatments. Furthermore, TeNT did not reduce hTau release under any condition. These results were confirmed in a mouse model where hTau was overexpressed in the retina, and hTau transfer to the brain was analysed. In agreement with the results obtained in vitro, P301S hTau release in vivo was significantly higher in control conditions compared to WT, and treatment with BoNT/A significantly reduced the release of P301S hTau. These findings suggest that specific SNARE proteins modulate hTau release both in vitro and in vivo, with pathologic mutant hTau behaving differently from WT hTau. The results demonstrated the potential of BoNT/A in the study of mechanisms of disease, and further research on BoNTs could provide novel insights into the machinery controlling synaptic tau release and help at identifying novel therapeutic targets for the treatment of tauopathies.
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