Steuer EL, Kemper LJ, Hlynialuk CJW, Leinonen-Wright K, Montonye ML, Lapcinski IP, Forster CL, Ashe KH, Liu P. Blocking Site-Specific Cleavage of Human Tau Delays Progression of Disease-Related Phenotypes in Genetically Matched Tau-Transgenic Mice Modeling Frontotemporal Dementia. Journal of Neuroscience. 2022;42(23):4737-4754. PMID: 35508385. DOI: 10.1523/JNEUROSCI.0543-22.2022.
Summary
This study tested whether preventing tau cleavage at Asp314 could alter disease progression in genetically matched tau-transgenic mice. The authors compared mice expressing cleavable P301L human tau with mice expressing a cleavage-resistant D314E variant. Blocking cleavage delayed tau accumulation in postsynaptic fractions, brain atrophy, hippocampal neurodegeneration, and spatial memory impairment. The results showed that site-specific tau cleavage contributes to disease-related phenotypes, while also indicating that this intervention delays rather than completely prevents pathology.
Key Findings
- A D314E mutation blocked site-specific tau cleavage.
- Cleavage resistance delayed memory impairment.
- Brain atrophy and hippocampal neurodegeneration were delayed.
- Tau phosphorylation and conformational pathology still progressed.
Impact on the Caspase-2/Tau Program
This paper strengthened the causal link between Asp314 tau cleavage and neurodegenerative phenotypes. It supports caspase-2 inhibition as a strategy to delay or reduce tau-mediated functional decline.