The Stress c-Jun N-terminal Kinase Signaling Pathway Activation Correlates with Synaptic Pathology and Presents A Sex Bias in P301L Mouse Model of Tauopathy

Lucia Buccarello, Clara Alice Musi, Arianna Turati, Tiziana Borsello

Research output: Contribution to journalArticle

Abstract

Pathological Tau (P-Tau) leads to dementia and neurodegeneration in tauopathies, including Alzheimer's disease. The P301L transgenic mice well mimic human tauopathy features; P-Tau localizes also at the dendritic spine level and this correlates with synaptic markers down-regulation. Importantly, tg females present a more severe pathology compared to male mice. We describe JNK activation in P301L-tg mice, characterizing by P-JNK and P-c-Jun, cleaved-Caspase-3, P-PSD95 and P-Tau (direct JNK-targets) increased levels in tg vs control mice. These data indicate that JNK stress pathway is involved in neuronal degenerative mechanisms of this mouse model. In addition, P-JNK level is higher in females compared to male tg mice, underlying a sexual dimorphism in the JNK pathway activation. The behavioral studies highlight that tg females present major cognitive and locomotor defects, strongly correlated with a more severe synaptic injury, in comparison to tg male. Notably, at the dendritic spine level, JNK is powerfully activated and its level reveals a sexual dimorphism that is coherent with behavioral defects and spine pathology. The P301L's synaptic pathology is characterized by a strong increase of P-PSD95/PSD95 and P-JNK/JNK ratios and by an augmented level of cleaved-Caspase-3 and a decrease of Drebrin level in the post-synaptic elements. These results suggest that JNK plays a key role in synaptopathy of P301L mice. Importantly, until now, there are any efficient treatments against synaptic pathology and JNK could represent an interesting target to tackle P-Tau-induced synaptic pathology. It will be important to test specific JNK inhibitors to verify their potential neuroprotective effect.

Original languageEnglish
Pages (from-to)196-205
Number of pages10
JournalNeuroscience
Volume393
DOIs
Publication statusPublished - Nov 21 2018

Fingerprint Dive into the research topics of 'The Stress c-Jun N-terminal Kinase Signaling Pathway Activation Correlates with Synaptic Pathology and Presents A Sex Bias in P301L Mouse Model of Tauopathy'. Together they form a unique fingerprint.

  • Cite this