Yoon SO, Park DJ, Ryu JC, Ozer HG, Tep C, Shin YJ, Lim TH, Pastorino L, Kunwar AJ, Walton JC, Nagahara AH, Lu KP, Nelson RJ, Tuszynski MH, Huang K.
JNK3 perpetuates metabolic stress induced by Aβ peptides.
Neuron. 2012 Sep 6;75(5):824-37.
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The mechanisms that lead to the pathology of Alzheimer’s disease (AD) are not completely understood. However, numerous hypotheses have been proposed to explain the main pathological features characteristic for the AD brain—among these, the increased production and accumulation of toxic amyloid-β (Aβ) species. Some of these hypotheses appear to hold when tested in cell culture, in animal models of AD, as well as when confronted with the real AD brain.
In their recent study, Yoon et al. came up with just such a hypothesis. They identify a pathway that could explain how an initial accumulation of oligomeric Aβ—probably caused by random fluctuations in the cell metabolism—could trigger a self-amplifying loop that produces and accumulates more toxic Aβ species. Briefly, the authors propose that the trigger of this pathway is a block of translation caused by an initial increase in extracellular Aβ oligomers. This is a stress, sensed by one of the neuron’s stress centers, the endoplasmic reticulum (ER), which unleashes a typical unfolded protein response (UPR) that activates the stress kinase, c-Jun N-terminal kinase 3 (JNK3). JNK3 then phosphorylates specific substrates—among them the Aβ precursor protein (APP). The phosphorylated APP (pAPP) is subjected to increased processing via the amyloidogenic pathway—a fact already known from previous studies (1)—likely through increased routing from the cell surface into endosomes, which provide a friendly, i.e., acidic, environment for secretase cleavage. In this way, a small, initial amount of oligomeric Aβ amplifies the generation and accumulation of toxic Aβ species. The authors' data also provide support for an interesting and logical pathway—involving activation of the kinase AMPK and inhibition of mTOR—for the initial events leading to the Aβ-triggered translational block.
Here, we would like to draw attention to two facts that appear essential for the increased production of Aβ, and which actually go hand in hand: the ER stress response and the phosphorylation of APP by JNK. In recent years, numerous studies (including ours) have pointed to stress—often mediated by an ER response—as the cause for neuronal degeneration and death in neurodegenerative diseases, including AD (2-12). Second, while it was known for some time that pAPP is a better substrate for amyloidogenic processing than non-phosphorylated APP (1), the fact that the phosphorylation of APP at Thr668 (numbering for the APP695 neuronal isoform) could be an obligatory event for the development of robust, AD-specific pathology is a finding of recent studies, including the one discussed here (1,14-16). These more recent studies (including one from our laboratory) also point to the role played by JNK—more specifically, JNK3—in the phosphorylation of Thr668 of APP and, likely, in the pathogenic process in AD (10,13,15). However, it has to be noted that the same residue (Thr668) can be—and actually is, under certain circumstances—phosphorylated by other kinases, including cyclin-dependent kinase 5 (Cdk5) (1,16,17). In this respect, of particular interest is the fact that a mouse model of AD-type neurodegeneration that reproduces fairly well both the amyloid and tau pathology is one that exogenously expresses p25, an activator of Cdk5 (18,19). We have also shown in cell culture that activation of Cdk5 leads to hyperphosphorylation of APP and neurodegeneration (17).
Finally, we would like to point out that—almost as a rule—it appears that the response to a cellular stress, rather than the stress itself, generates the toxic Aβ species, which accumulate and oligomerize. The initial stress may vary; it can be an oxidative stress, a block of translation, or an impeded axonal transport, as we recently proposed (10). In our recently published model, the block of transport leads to the accumulation of APP and recruitment to APP of the active JNK complex in neuronal soma at the ER. This leads to the phosphorylation of APP, followed by its amyloidogenic processing and the release of Aβ in the ER lumen, where it accumulates and oligomerizes. Certainly, there are many stress-activated pathways that can trigger abnormal production and accumulation of toxic Aβ species, and they all, in principle, could affect the metabolism of APP, and—if stress is sustained—could lead to AD pathology. For now, it appears that a number of these pathways involve an ER response to a stress, and lead to the phosphorylation of APP.
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Under diverse stress conditions, such as a perturbed calcium homeostasis, the normal function of the endoplasmic reticulum (ER) is impaired, leading to a phenomenon known as ER stress. To reestablish homeostasis and normal ER function, mammalian cells evolved a coordinated response of protein signaling pathways and transcription factors termed the unfolded protein response (UPR). This adaptive response initiates ER-to-nucleus signaling cascades that involve the transcriptional upregulation of genes that increase the ER folding capacity, protein quality control, and degradation of terminally misfolded proteins. In addition, the influx of newly synthesized proteins into the ER is reduced through induction of general translational arrest. This reduction in the global rate of translation is one of the earliest events in the UPR, and it was reported to inhibit long-term potentiation and memory acquisition. Accordingly, recent observations suggest that deregulation of the UPR, or chronic ER stress, is a fundamental pathological event in many neurodegenerative disorders, such as Alzheimer’s disease (AD).
ER stress markers have been found in postmortem samples from patients affected with AD, as well in cellular and animal models of this brain disorder. Pharmacological strategies and genetic manipulation in cellular and animal disease models have provided promising results concerning the contribution of ER stress to the neurodegenerative process. Several in-vitro studies support the finding that UPR activation and ER stress are induced by the amyloid-β (Aβ) peptide. We found that Aβ oligomers, which have been suggested to be the main neurotoxins in AD, impair ER calcium homeostasis and activate the UPR, leading to an ER stress-mediated apoptotic cell death pathway in cortical and hippocampal neurons (Resende et al., 2008; Costa et al., 2012). Yoon and colleagues now provide clear evidence that Aβ oligomers block translation, leading to widespread ER stress, and they clarified the molecular mechanisms implicated in these events. Through an elegant and well-designed study that used several cellular and animal models, as well as AD brain samples, the authors demonstrated that oligomeric Aβ-induced translational block and subsequent ER stress activates JNK3, which in turn phosphorylates APP, facilitating its endocytosis and subsequent amyloidogenic processing and Aβ42 production. In a familial AD mouse model, Yoon et al. further demonstrated that JNK3 deletion reduces Aβ42 levels and plaque loads, increases neuronal numbers, and improves cognition, thus implicating ER stress-mediated JNK3 activation in the neurodegenerative process and cognitive deficits induced by Aβ oligomers in AD.
Yoon and colleagues found that AMP-activated protein kinase (AMPK) activation and subsequent mammalian target of rapamycin inhibition occur upstream of Aβ-induced translational block and subsequent ER stress, showing that perturbation of energy metabolism plays a major causal role in the synaptotoxic effect of Aβ oligomers, and supporting the idea that metabolic deficits have a major role during preclinical AD. Indeed, brain imaging studies demonstrated that cerebral glucose utilization is reduced in the brains of AD patients and, more importantly, in mild cognitive impairment (MCI) subjects. These metabolic alterations that occur in the initial stages of the pathology seem to arise from the deleterious effect of Aβ in mitochondria. Aβ has been shown to accumulate in the mitochondria (resulting, at least in part, from APP processing within this organelle) and to induce structural and functional alterations that culminate in ATP depletion, oxidative stress, and activation of cell death pathways.
Based on the present findings, the authors propose that a plausible explanation for AMPK activation by Aβ oligomers is the perturbation of intracellular calcium homeostasis and subsequent activation of kinases such as calmodulin kinase. This hypothesis is supported by recent studies from our lab demonstrating that ER stress occurs downstream of activation of the GluN2B subunit of the N-methyl-D-aspartate receptor (NMDAR) and perturbation of intracellular calcium levels in neuronal cultures treated with Aβ oligomers (Costa et al., 2012; Ferreira et al., 2012). The paper by Yoon et al. suggests that Aβ oligomers trigger a positive feedback loop during the initial stages of the disease that culminates in synaptic dysfunction and cognitive deficits. As demonstrated in the paper, oligomeric Aβ induces translational block and ER stress through metabolic impairment with AMPK activation, which in turn increases Aβ levels by a JNK3-mediated mechanism, leading to cognitive alterations. Aβ might directly potentiate the initial mitochondrial dysfunction/metabolic impairment that can be further enhanced by the deadly ER-mitochondria calcium transfer that we demonstrated to occur during ER stress conditions triggered by Aβ (Ferreiro et al., 2008; Costa et al., 2010).
Finally, the authors identify the ER stress-activated JNK3 as a promising new target of therapeutic intervention in AD. Targeting brain UPR could be a potential therapeutic avenue for the treatment of AD; however, the functional implications of UPR activation and the clinical outcome are presently unknown. Activation of the adaptive branches of the UPR can protect neurons by increasing protein folding, protein quality control, and autophagy, but, on the other hand, UPR activation may represent a signal for neurodegeneration triggered by chronic ER stress, resulting in irreversible neuronal damage and apoptosis. Therefore, the long-term consequences of targeting UPR for reducing neuronal loss must be properly addressed. Targeting JNK3, as proposed, might avoid these potentially deleterious side effects, since its activation occurs downstream of UPR activation.
By gaining a better understanding of the mechanisms underlying UPR activation and how it affects the neurodegenerative process in this disease, we should gain new insights into the pathological mechanisms, thus providing interesting and novel targets for disease intervention.
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