Affiliations: [a] Istituto di Ricerche Farmacologiche “Mario Negri”, Milano, Italy | [b] Dipartimento di Neuroscienze, Università di Tor Vergata, Rome, Italy CNR, Rome, Italy | [c] Proteomics Unit NeuroBioGen Lab-Memory Clinic, IRCCS Centro S. Giovanni di Dio-Fatebenefratelli, Brescia, Italy | [d] NICO, Scientific Institute of the Cavalieri-Ottolenghi Foundation Neuroscience Institute of Turin, Orbassano (To), Italy
Correspondence:
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Correspondence to: Tiziana Borsello, Neuronal Death and Neuroprotection Laboratory, Neuroscience Department, Istituto di Ricerche Farmacologiche “Mario Negri”, Via La Masa 19, 20156 Milano, Italy. Tel.: +39 02 39014469/39014592; Fax: +39 02 3546277; E-mail: tiziana.borsello@marionegri.it.
Note: [1] These two authors contributed equally to this work.
Note: [2] Present Address: DZNE - German Center for Neurodegenerative Diseases, Schillerstrasse 44, 80336 Munich, Germany.
Abstract: Alzheimer's disease (AD) is a major clinical concern, and the search for new molecules to combat disease progression remains important. One of the major hallmarks in AD pathogenesis is the hyperphosphorylation of tau and subsequent formation of neurofibrillary tangles. Several kinases are involved in this process. Amongst them, c-Jun N-terminal kinases (JNKs) are activated in AD brains and are also associated with the development of amyloid plaques. This study was designed to investigate the contribution of JNK in tau hyperphosphorylation and whether it may represent a potential therapeutic target for the fight against AD. The specific inhibition of JNK by the cell permeable peptide D-JNKI-1 led to a reduction of p-tau at S202/T205 and S422, two established target sites of JNK, in rat neuronal cultures and in human fibroblasts cultures. Similarly, D-JNKI-1 reduced p-tau at S202/T205 in an in vivo model of AD (TgCRND8 mice). Our findings support the fundamental role of JNK in the regulation of tau hyperphosphorylation and subsequently in AD pathogenesis.
Keywords: Alzheimer's disease, D-JNKI-1, JNK mitogen-activated protein kinases, phosphorylation, tau protein
