Co-expression of truncated and full-length tau induces severe neurotoxicity

Abundant tau inclusions are a defining hallmark of several human neurodegenerative diseases, including Alzheimer’s disease. Although studied widely, the relevance of tau fragmentation for the neurodegenerative process has remained unclear. Here we found that co-expression of truncated and full-length human tau in mice provoked the formation of soluble high-molecular weight tau, the failure of axonal transport, clumping of mitochondria, disruption of the Golgi apparatus, and missorting of synaptic proteins. This was associated with extensive nerve cell dysfunction and severe paralysis by the age of 3 weeks. When the expression of truncated tau was halted, most mice recovered behaviorally and functionally. In contrast, co-expression of full-length tau isoforms did not result in paralysis. Truncated tau thus induces extensive but reversible neurotoxicity in presence of full-length tau through the formation of non-filamentous high-molecular weight tau aggregates. Targeting tau fragmentation may provide a novel approach for the treatment of human tauopathies