The Loss of c-Jun N-Terminal Protein Kinase Activity Prevents the Amyloidogenic Cleavage of Amyloid Precursor Protein and the Formation of Amyloid PlaquesIn Vivo

Abstract

Phosphorylation plays a central role in the dynamic regulation of the processing of the amyloid precursor protein (APP) and the production of amyloid-␤ (A␤), one of the clinically most important factors that determine the onset of Alzheimer's disease (AD). This has led to the hypothesis that aberrant A␤ production associated with AD results from regulatory defects in signal transduction. However, conflicting findings have raised a debate over the identity of the signaling pathway that controls APP metabolism. Here, we demonstrate that activation of the c-Jun N-terminal protein kinase (JNK) is essential for mediating the apoptotic response of neurons to A␤. Furthermore, we discovered that the functional loss of JNK signaling in neurons significantly decreased the number of amyloid plaques present in the brain of mice carrying familial AD-linked mutant genes. This correlated with a reduction in A␤ production. Biochemical analyses indicate that the phosphorylation of APP at threonine 668 by JNK is required for ␥-mediated cleavage of the C-terminal fragment of APP produced by ␤-secretase. Overall, this study provides genetic evidence that JNK signaling is required for the formation of amyloid plaques in vivo. Therefore, inhibition of increased JNK activity associated with aging or with a pathological condition constitutes a potential strategy for the treatment of AD.

SPATA2 regulates the activation of RIPK1 by modulating linear ubiquitination

“…6A). Furthermore, we explored the involvement of MKK4 or MKK7, two known activators of JNK (Yan et al 1994;Tournier et al 1999;Mazzitelli et al 2011). Upon TNFα stimulation, the phosphorylation of MKK4 was significantly increased in Spata2-deficient cells, while p-MKK7 was undetectable (Fig.…”

Enhanced Functional Genomic Screening Identifies Novel Mediators of Dual Leucine Zipper Kinase-Dependent Injury Signaling in Neurons

“…While we have consistently failed to observe survival-promoting activity with p38 inhibitors (data not shown), both kinase screens identified knockdown of MKK4 and MKK7, both JNK kinases, as survival-promoting. In order to confirm a role for MKK4/7 and JNK1-3 in RGC cell death, we isolated primary RGCs from Mkk4/7 (Mazzitelli et al, 2011)t and Jnk1-3 (Xu et al, 2011) conditional knockout mice, and transduced them with Cre or GFP adenovirus. As expected, deletion of Jnk1, Jnk2 and Jnk3 (Figure 4B) or Mkk4 and Mkk7 (Figure 4C) increased RGC survival, more than individual knockout of Mkk4 or Mkk7 (data not shown).…”

“…SpCas9 knockin mice ( Rosa26 locus ) were obtained from Jackson labs (stock 026179). Mice with the following alleles: Dlk fl/fl (Miller et al, 2009, RRID: MGI:5440728), Mkk4 fl/fl Mkk7 fl/fl (Mazzitelli et al 2011), Jnk1 fl/fl Jnk2 −/− Jnk3 −/− (Xu et al, 2011), Mef2a fl/fl and Mef2a fl/fl Mef2c fl/fl Mef2d fl/fl (Akhtar et al, 2012), Sox11 fl/fl (Wang et al, 2013; RRID: MGI:5510984) and Atf2 fl/fl (Shah et al, 2010) were generously provided by the respective investigators. In cases where a single, pure-breeding genotype received different treatments, littermates were randomly assigned to experimental groups.…”

Amyloid-β precursor protein: Multiple fragments, numerous transport routes and mechanisms

“…Because APP fragments appear to be transported separately, the modifiers of APP processing are likely to alter APP’s downstream transport. Of particular importance is the phosphorylation of APP at Thr 668 (numbering in APP695) [61, 62], since this modification facilitates the amyloidogenic processing of APP by both β- and γ-secretase [39, 63]. This phosphorylation also specifies the recruitment of kinesin-1 via JIP-1 [45], and possibly the recruitment of myosin motors, which is determinant for targeting pAPP to distal ends in the growth cone [14].…”