Activation of c-Jun N-Terminal Kinase and p38 in an Alzheimer's Disease Model Is Associated with Amyloid Deposition

Abstract

The mechanisms by which neurons and synapses are lost in Alzheimer's disease (AD) are not completely understood. To characterize potential signaling events linked to AD pathogenesis, activation-specific antibodies were used to examine mitogen-activated protein kinase (MAPK) kinase pathways at various ages in mice transgenic for human amyloid precursor protein-695 with the Swedish familial AD mutations (Tg2576) and homozygous for a P264L familial AD mutation introduced by targeting of the presenilin-1 gene (PS1(P264L)). Although the c-Jun N-terminal kinase (JNK) and p38 pathways were significantly activated in the cortex at both 7 and 12 months of age, there was no significant activation of the extracellular signal-regulated kinase pathway. MAPK kinase-4, an upstream activator of JNK, was also significantly activated at 7 and 12 months, whereas c-Jun, a downstream effector of JNK-associated apoptotic signaling, was not induced. The lack of c-Jun activation is consistent with the absence of neuronal loss in both cortex and hippocampal CA1 at 12 months. The JNK activation was localized to amyloid deposits, within neurites containing phosphorylated tau. Synaptophysin was quantified biochemically as a measure of synaptic integrity and was significantly reduced in an age-dependent manner in the Tg2576/PS1(P264L) cortex but not in either PS1(P264L) or Tg2576 cortex. Stress-responsive MAP kinase pathways were activated in the brain of the Tg2576/PS1(P264L) AD model, and this activation was coincident with the age-dependent increase in amyloid deposition, tau phosphorylation, and loss of synaptophysin.

Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein

“…These mice showed some similarities with the Tg2576 + PS1P264L double transgenic mouse model of Savage et al (2002) as both AD models showed increased JNK pathway activation, a feature displayed by the human AD brain (Zhu et al, 2001;Savage et al, 2002). These results support the known strong correlation between hCTF99 or its products and increased JNK pathway activation in the pathogenesis of AD.…”

“…brain shows phospho-JNK up-regulation (Zhu et al, 2001;Savage et al, 2002) prompted us to examine the levels of phospho-JNK, -ERK, -p38 MAPKs, and phospho-c-Jun in the Tg-hCTF99/B6 brain. It was found that the levels of phospho-JNK and phospho-c-Jun in the whole cerebrum homogenate of Tg-hCTF99/B6 at 15 months were notably higher than those of age-matched controls, whereas the expressions of JNK1, JNK2, JNK3, phospho-ERK, and phospho-p38 were not significantly changed (Fig.…”

Herp Stabilizes Neuronal Ca2+ Homeostasis and Mitochondrial Function during Endoplasmic Reticulum Stress

“…Another pro-apoptotic signaling cascade induced by ER stress is the activation of JNK/c-Jun, which is attenuated by Herp. Since activation of these cascades is involved in A␤-induced neurotoxicity (10,27,49), Herp may protect cells exposed to A␤ by suppressing caspase 12 and JNK activation.…”

N-cadherin Regulates p38 MAPK Signaling via Association with JNK-associated Leucine Zipper Protein

“…For example, both p38 MAPK and its upstream kinase MKK6 are activated in AD brain tissue as demonstrated by immunohistochemistry (17,18). Activation of the p38 MAPK signaling is also reported in an AD-relevant animal model (19). Moreover, a previous report demonstrated that A␤ employs synaptic depression to drive endocytosis of synaptic AMPA receptor by activating p38 MAPK (20).…”