Neuronal microtubule-associated protein (MAP) tau is implicated in neurodegenerative diseases termed tauopathies. Tau can assemble into a cohesive layer termed microtubule envelope, which protects the microtubule surface against microtubule-severing enzymes. In neurodegeneration, tau aggregates presumably via dissociation from microtubules, followed by microtubule degradation. Mechanisms underlying these processes are, however, unclear. Here, we combine in vitro reconstitution and molecular modeling to describe how metabolites, which are implicated in neurodegenerative processes, regulate the tau envelope formation and integrity. Our results suggest that the dynamics and protective function of tau envelopes are sensitive to neurodegeneration-related metabolites, and their fluctuations can lead to disintegration of microtubules.