Conserved synaptic modifications by humanized tau through diverse isoform- and mutation-specific intracellular interactions

Mutations in the microtubule-binding protein tau are considered causal for a diverse group of neurodegenerative diseases collectively referred to as primary tauopathies. Specific tauopathies are associated with different mutations, distinct tau isoforms, manifest in unique cellular and circuit-wide patterns of degeneration, and present with specific clinical symptoms and trajectories. The mechanisms that link variations in the primary tau protein structure to distinct forms of neural circuit dysfunction remain largely unknown. Here, we created an orthogonal viral resource to systematically examine the impact of expressing humanized tau isoforms harboring different disease-relevant mutations in excitatory pyramidal cells from the mouse prelimbic cortex. We used these reagents to show that expression of mutant humanized tau (hTau) as either of two isoforms produced very similar patterns of circuit-specific synaptic disconnection on cortical projection neurons. However, mass spectrometry revealed that the interactomes of these different tau species varied markedly as functions of isoform, mutation, and subcellular location. We validated the functional relevance of increased hTau interactions with mitochondrial proteins in induced neurons differentiated from Ngn2-iPSCs expressing different hTau constructs. These results suggest different disease-relevant hTau proteins likely use distinct mechanisms to drive a highly stereotyped form of synapse loss in cortical neurons.