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

Expressing mutant humanized tau isoforms in mouse prelimbic cortex excitatory pyramidal cells produces highly similar circuit-specific synaptic disconnection patterns, despite markedly different interactomes.

• Why it matters: Primary tauopathies link specific tau mutations and isoforms to distinct circuit dysfunction, but how tau structure shapes synaptic degeneration mechanisms is unclear.
• What they did: The team built an orthogonal viral resource to express humanized tau isoforms with different disease-relevant mutations in mouse prelimbic cortex pyramidal neurons, then used mass spectrometry to compare isoform-, mutation-, and location-specific interactomes.
• The result: Increased interactions between mutant hTau and mitochondrial proteins were functionally validated in induced neurons from Ngn2-iPSCs expressing different hTau constructs, implying isoform- and mutation-specific mechanisms behind stereotyped synapse loss.

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