Inhibition of c-Jun kinase provides neuroprotection in a model of Alzheimer's disease
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.
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- 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.
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Present address: Proteostasis Therapeutics, Cambridge, MA 02139, USA.