Elsevier

Neurobiology of Disease

Volume 39, Issue 3, September 2010, Pages 311-317
Neurobiology of Disease

Inhibition of c-Jun kinase provides neuroprotection in a model of Alzheimer's disease

https://doi.org/10.1016/j.nbd.2010.04.015Get rights and content

Abstract

The c-Jun N-terminal kinase (JNK) pathway potentially links together the three major pathological hallmarks of Alzheimer's disease (AD): development of amyloid plaques, neurofibrillary tangles, and brain atrophy. As activation of the JNK pathway has been observed in amyloid models of AD in association with peri-plaque regions and neuritic dystrophy, as we confirm here for Tg2576/PSM146L transgenic mice, we directly tested whether JNK inhibition could provide neuroprotection in a novel brain slice model for amyloid precursor protein (APP)-induced neurodegeneration. We found that APP/amyloid β (Aβ)-induced neurodegeneration is blocked by both small molecule and peptide inhibitors of JNK, and provide evidence that this neuroprotection occurs downstream of APP/Aβ production and processing. Our findings demonstrate that Aβ can induce neurodegeneration, at least in part, through the JNK pathway and suggest that inhibition of JNK may be of therapeutic utility in the treatment of AD.

Introduction

Multiple and distinct pathologies characterize Alzheimer's disease (AD), including deposition of amyloid plaques, formation of neurofibrillary tangles and neurodegeneration (Huang and Jiang, 2009). Development of AD therapeutics has largely attempted to address these pathologies separately, but approaches that influence multiple pathologies may be advantageous. One pathway that potentially links all of the pathological hallmarks of AD is that through the c-jun N-terminal kinases (JNKs). The activation of JNKs leads to the phosphorylation of transcription factors controlling the apoptotic process (Dhanasekaran and Reddy, 2008), thereby resulting in cell death in multiple neurodegenerative disorders (Bogoyevitch et al., 2004). Furthermore, the JNK pathway can be activated by amyloid β (Aβ) peptides (Morishima et al., 2001) and has also been reported to regulate the phosphorylation of amyloid precursor protein (APP) leading to modulation of Aβ levels (Colombo et al., 2009, Colombo et al., 2007). Finally, there is strong evidence that JNKs can phosphorylate tau in vitro (Yoshida et al., 2004).

The JNK pathway has been shown to be active in preclinical models of AD, including Tg2576 and Tg2576/PS1P264L transgenic mice by biochemical and immunohistochemical analyses (Flood et al., 2002, Puig et al., 2004). However, to date, there have been no reports on manipulation of the JNK pathway being directly tested in a model of AD to ask whether JNK activation may contribute to disease pathogenesis, and whether its inhibition may have therapeutic potential.

Thus, in the present study, we first used a transgenic animal model of AD, with mutations in presenilin and APP resulting in excessive Aβ generation and amyloid plaque formation, to examine the potential association of JNK activation with amyloid histopathogenesis. We then directly examined whether inhibition of JNK pathways could provide benefit in a novel AD model system in which particle-mediated gene transfer, or biolistics, is used to present an acute challenge of the amyloid cascade to ex vivo brain slice explants. This brain slice model has the ability to maintain the complex interplay among different resident cell types and their local connectivity, while retaining the ability to further investigate and manipulate the JNK pathways in the context of APP-induced neurodegeneration. Together, our findings from these in vivo and ex vivo models link amyloid, tau and neurodegenerative pathologies through the JNK pathway, and suggest that inhibition of JNK activity could provide therapeutic benefit in the context of AD.

Section snippets

Antibodies and chemicals

Antibodies against amyloid β (6E10) and pan-axonal neurofilament marker (SMI-312) were purchased from Covance (Princeton, NJ), anti-phosphorylated JNK from Cell Signaling Technology (Danvers, MA), and anti-BACE1 (PA1-575) from Affinity Bioreagents (Rockford, IL). WYGSI-04 (Pu et al., 2009) was synthesized at Wyeth, SP600125 was purchased from Calbiochem (San Diego, CA), and JNK inhibitory peptide (L-JNKi1) and control peptides were purchased from EMD Chemicals (Gibbstown, NJ).

Immunofluorescence labeling

Animal protocols

JNK activation in Tg2576/PS1M146L mice co-localizes with amyloid plaques and markers of neurodegeneration

To determine whether activation of the JNK pathway may be important for neurodegeneration in Alzheimer's disease, and whether inhibition of the JNK pathway could be considered as a therapeutic approach, we sought to study a transgenic animal model with overt amyloid pathology. The Tg2576/PS1M146L mouse carries the APP-Swedish mutation (KM670/671NL) and the presenilin mutation M146L, leading to highly elevated Aβ levels (Holcomb et al., 1998). In this mouse model, extensive amyloid plaque

Discussion

Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and stroke are typically late-onset conditions with multiple potential causes, pathological hallmarks, and dysregulation of multiple pathways. Therefore, across a spectrum of neurodegenerative disorders there is increasing appreciation that targeting a single mechanism may not be sufficient to halt the progression of neurodegeneration and provide disease modification. Most notably, development of therapeutics against

Acknowledgments

This work was in part funded by NIH grant NS048181.

References (43)

  • A. Schneider et al.

    Tau-based treatment strategies in neurodegenerative diseases

    Neurotherapeutics

    (2008)
  • C. Shen

    Hydrogen peroxide promotes Aβ production through JNK-dependent activation of γ-secretase

    Vol.

    (2008)
  • E. Tamagno

    JNK and ERK1/2 pathways have a dual opposite effect on the expression of BACE1

    Neurobiol. Aging

    (2009)
  • E.R. Vardy

    Proteolytic mechanisms in amyloid-beta metabolism: therapeutic implications for Alzheimer's disease

    Trends Mol. Med.

    (2005)
  • J. Vogel

    The JNK pathway amplifies and drives subcellular changes in tau phosphorylation

    Neuropharmacology

    (2009)
  • B.V. Zlokovic

    New therapeutic targets in the neurovascular pathway in Alzheimer's disease

    Neurotherapeutics

    (2008)
  • B.L. Bennett

    SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase

    Proc. Natl. Acad. Sci. U. S. A.

    (2001)
  • T. Borsello

    A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia

    Nat. Med.

    (2003)
  • S. Brecht

    Specific pathophysiological functions of JNK isoforms in the brain

    Eur. J. Neurosci.

    (2005)
  • S. Cho

    Brain slices as models for neurodegenerative disease and screening platforms to identify novel therapeutics

    Curr. Neuropharmacol.

    (2007)
  • A. Colombo

    The TAT-JNK inhibitor peptide interferes with beta amyloid protein stability

    Cell Death Differ.

    (2007)
  • Cited by (74)

    • Kinase inhibition in Alzheimer’s disease

      2022, Protein Kinase Inhibitors: From Discovery to Therapeutics
    View all citing articles on Scopus
    1

    These authors contributed equally to this work.

    2

    Present address: Signum Biosciences, Monmouth Junction, NJ 08852, USA.

    3

    Present address: U.S. Food and Drug Administration, Silver Springs, MD 20993, USA.

    4

    Present address: Pfizer Global Research and Development, Groton, CT 06340, USA.

    5

    Present address: Proteostasis Therapeutics, Cambridge, MA 02139, USA.

    View full text