C. elegans detects toxicity of traumatic brain injury generated tau

NEUROBIOLOGY OF DISEASE

卷:153

Article

Zanier, Elisa R.¹  Barzago, Maria Monica²  Vegliante, Gloria¹  Romeo, Margherita²  Restelli, Elena¹  Bertani, Ilaria¹  Natale, Carmina^1,2  Colnaghi, Luca^1,2  Colombo, Laura²  Russo, Luca²  Micotti, Edoardo¹  Fioriti, Luana¹  Chiesa, Roberto¹  Diomede, Luisa² 

[1] Ist Ric Farmacol Mario Negri IRCCS, Dept Neurosci, Via Mario Negri 2, I-20156 Milan, Italy

[2] Ist Ric Farmacol Mario Negri IRCCS, Dept Mol Biochem & Pharmacol, Via Mario Negri 2, I-20156 Milan, Italy

关键词: Tau;    Tauopathy;    Traumatic brain injury;    Caenorhabditis elegans;   

DOI  :  10.1016/j.nbd.2021.105330

来源: Elsevier

【 摘 要 】

Traumatic brain injury (TBI) is associated with widespread tau pathology in about 30% of patients surviving late after injury. We previously found that TBI in mice induces the formation of an abnormal form of tau (tauTBI) which progressively spreads from the site of injury to remote brain regions. Intracerebral inoculation of TBI brain homogenates into na?ve mice induced progressive tau pathology, synaptic loss and late cognitive decline, suggesting a pivotal role of tauTBI in post-TBI neurodegeneration. However, the possibility that tauTBI was a marker of TBI-associated neurodegeneration rather than a toxic driver of functional decline could not be excluded. Here we employed the nematode C. elegans as a biosensor to test the pathogenic role of TBI generated tau. The motility of this nematode depends on efficient neuromuscular transmission and is exceptionally sensitive to the toxicity of amyloidogenic proteins, providing a tractable model for our tests. We found that worms exposed to brain homogenates from chronic but not acute TBI mice, or from mice in which tauTBI had been transmitted by intracerebral inoculation, had impaired motility and neuromuscular synaptic transmission. Results were similar when worms were given brain homogenates from transgenic mice overexpressing tau P301L, a tauopathy mouse model, suggesting that TBI-induced and mutant tau have similar toxic properties. P301L brain homogenate toxicity was similar in wild-type and ptl-1 knock-out worms, indicating that the nematode tau homolog protein PTL-1 was not required to mediate the toxic effect. Harsh protease digestion to eliminate the protein component of the homogenates, pre-incubation with anti-tau antibodies or tau depletion by immunoprecipitation, abolished the toxicity. Homogenates of chronic TBI brains from tau knock-out mice were not toxic to C. elegans, whereas oligomeric recombinant tau was sufficient to impair their motility. This study indicates that tauTBI impairs motor activity and synaptic transmission in C. elegans and supports a pathogenic role of tauTBI in the long-term consequences of TBI. It also sets the groundwork for the development of a C. elegans-based platform for screening anti-tau compounds.