Therapeutic targeting of pathogenic presynaptic Tau in human neurons in a chimeric Alzheimer’s Disease mouse model

Alzheimer’s disease is a progressive neurodegenerative disorder, and is characterized by amyloid beta plaques, neurofibrillary tangles and granulovacuolar degeneration (Scheltens et al. 2021). An early deficit in AD is synaptic dysfunction, which closely correlates to cognitive decline (Dekosey et al. 1990; Terry et al. 1991). Tau pathology plays a causal role in synaptic dysfunction (Zhou et al. 2017; Mclnnes et al. 2018) as it binds to synaptic vesicles via Synaptogyrin-3 and thereby restricts synaptic vesicle mobility (Mclnnes et al. 2018; Figure 1). Lowering Synaptogyrin-3 levels in flies (in vivo) and mouse primary neurons (in vitro) with Tau-pathology reduces Tau-synaptic vesicle interactions and consequently rescues vesicular mobility and neurotransmitter release (Mclnnes et al. 2018). In addition, lowering Synaptogyrin-3 in a Tauopathy mouse rescues synaptic loss, neurotransmission and cognitive deficits (Largo-Barrientos et al. 2021). In this project, I will study the effect of lowering Synaptogyrin-3 levels in human neurons that are exposed to Ab pathology. I will implant human-derived neurons in a mouse with Amyloid Beta pathology using a novel chimeric Alzheimer model created by my co-host lab (Espuny-Camacho et al. 2017). I expect that lowering of Synaptogyrin-3 in human transplanted neurons will overcome Tau-mediated synaptic loss and reduce neurodegeneration.