JNK Plays a Key Role in Tau Hyperphosphorylation in Alzheimer's Disease Models

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.

c-Jun N-terminal Kinase Regulates Soluble Aβ Oligomers and Cognitive Impairment in AD Mouse Model

“…This peptide prevents exclusively the action of JNK on its JNK binding domain (JBD)-dependent targets, resulting in a partial inhibition of the enzyme that is nevertheless activated and thus able to phosphorylate JBD-independent targets (41). D-JNKI1 crosses the blood-brain barrier successfully (19,23,42), it is composed of D-amino acids that are not easily degraded by proteases and is not immunogenic (D-amino acid form is not recognized).…”

β2 Adrenergic Receptor, Protein Kinase A (PKA) and c-Jun N-terminal Kinase (JNK) Signaling Pathways Mediate Tau Pathology in Alzheimer Disease Models

“…In addition, the JNK pathway amplifies and drives subcellular changes in tau phosphorylation (1) and plays key role in tau phosphorylation in AD models (33). GSK3␤ is a major physiological tau kinase that requires priming phosphorylation at Ser-404 to further phosphorylate tau at paired helical filament 1 (34).…”

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

“…These observations highlight JNKs as targets for pharmaceutical intervention to ameliorate stroke and epilepsy, Alzheimer's disease, Parkinson's disease, and Huntington's disease (reviewed in reference 2). JNKs may contribute to the earliest phases of Alzheimer's disease (AD); the Tau protein is a well-established substrate of JNK, and the phosphorylation of Tau might occur at the earliest stages of synaptic dysfunction and microtubule disassembly, thus preceding cognitive deficits in AD models (265). The inhibition of JNK activity (causing microtubule disassembly, Tau release, and/or aggregation) may thus represent one option to prevent the formation of neurofibrillary tangles and so should be further tested for its efficacy as a treatment modality.…”

“…S1C). These cytoskeletal JNK substrate proteins include those associating with microtubules (DCX [260][261][262], MAP1B [180,263], MAP2 [264], Tau [265], and WDR62 [213]), the actin cytoskeleton (MARCKSL1 [266] and SMTL2 [267]), or focal adhesions (paxillin [268,269] and ␤-catenin [270][271][272]). In addition, JNK-mediated phosphorylation of additional proteins may also direct vesicular transport (through phosphorylation of JIP1 and ␤-APP [104,217]), as well as the exocytosis of specialized, Glut4-containing vesicles (through insulin-stimulated phosphorylation of IRS1 and IRS2 [273,274]).…”