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Written by Zhao Yingying, edited by Wu Qinghua, Wang Sizhen Alzheimer's disease (AD) and Parkinson's disease (PD) are common neurodegenerative diseases.
Such diseases are caused by the loss of neurons and/or their myelin sheaths, which worsen over time, leading to neurological dysfunction [1].
Due to the multiple factors and complexity of the etiology of these diseases, there is still no best treatment drug.
In the past 20 years, scientists have done a lot of research on the pathogenesis of neurodegenerative diseases, and new mechanisms have been continuously reported.
Studies have found that tau protein hyperphosphorylation, β-amyloid (Aβ) deposition, acetylcholine deficiency, synapse loss, dendritic pruning, etc.
are closely related to neurodegenerative diseases [2-3].
However, the master switch that regulates these complex mechanisms, that is, the upstream regulatory signal protein, is still unclear, so that there has been no major breakthrough in the treatment of neurodegenerative diseases by target molecules.
On May 25, 2021, the team of Professor Wu Qinghua and Professor Kamil Kuca from the Joint Laboratory of Toxicology of Yangtze University-Hradec Kralove University (Czech Republic) published an online publication entitled "Hypothesis: JNK Signaling is" in Alzheimer's & Dementia.
a Therapeutic Target of Neurodegenerative Diseases" Scientific Hypothesis Article (Review Article).
Based on a large amount of data from cell and animal experiments, the team comprehensively analyzed the mechanism of JNK signaling in the pathogenesis of neurodegenerative diseases, and put forward the hypothesis: JNK is a potential target for the treatment of neurodegenerative diseases.
This article provides an in-depth analysis of how to effectively verify this scientific hypothesis and the challenges it faces.
This hypothesis provides new ideas for the development of Alzheimer's disease target drugs and precision molecular treatment of such diseases.
Background JNK, also known as stress-activated protein kinase, is another subtype of MAPK (mitogen-activated protein kinase) signaling pathway in mammalian cells.
JNK protein kinase is encoded by three genes.
The JNK1 and JNK2 genes are widely expressed throughout the body, while the JNK3 gene is mainly expressed in the brain and less expressed in the heart and testis [4].
JNK1/2 is involved in the regulation of immune cells and the development of the embryonic nervous system, while JNK3 is the main subtype activated by stress stimulation and is mainly involved in the process of neurodegeneration [3,5].
Studies have shown that the activation of JNK is not only related to the hyperphosphorylation of tau protein in AD and other neurodegenerative diseases, but also involved in the production and accumulation of Aβ [6-8].
JNK can phosphorylate tau protein at multiple sites and cause it to dissociate from microtubules, which ultimately leads to the formation of neurofibrillary tangles [6,9].
Among them, JNK3 can strongly autophosphorylate and promote tau hyperphosphorylation [10].
It is worth noting that JNK3 promotes the production of Aβ42, the main component of senile plaques, through phosphorylation of amyloid precursor protein (APP); in turn, Aβ can induce JNK activation, thereby forming a positive feedback loop [7-8].
The JNK signaling pathway is also related to the progressive loss of dopaminergic neurons in the substantia nigra, which is the main cause of PD [11].
In addition, the physiologically active JNK modulates synaptic strength and promotes synaptic plasticity through phosphorylation of different substrates [4].
Although the basal level of JNK activity is necessary for inducing synaptic plasticity, overactivation of JNK induced by stress is harmful to synaptic plasticity and may lead to memory defects and neurodegeneration [5,12].
The mechanism of JNK in the formation of neurofibrillary tangles (picture quoted from: Zhao et al.
Alzheimer's & Dementia2021; 1-7) hypothesis that the JNK signaling pathway affects the function of neurons, leading to nerve damage and subsequent spatial learning And memory impairment.
For example, treatment of JNK3 knockout mice with the glutamate receptor agonist kainic acid found that the degeneration of hippocampal neurons in the mice was reduced [13].
In addition, treatment of primary rat cortical neurons with JNK inhibitors can effectively prevent the down-regulation of the anti-apoptotic proteins Bcl-w and Bcl-xL, indicating that JNK is involved in the neuronal death pathway [14].
The memory of JNK1 gene-deficient mice and the spinous structure of hippocampal neuron dendrites have been destroyed, indicating that JNK is essential in synaptic plasticity [5].
However, continuous activation of JNK is harmful to synaptic plasticity [12].
In addition, it was found in the H4-APPsw cell line that inhibition of JNK activity can prevent the phosphorylation of APP at Thr 668, thereby greatly reducing Aβ fragments; this fully proves that JNK participates in the phosphorylation of APP at Thr668.
This promotes the production of Aβ protein [15].
Similarly, the inhibition of JNK can also prevent the phosphorylation of tau in rat cortical neurons and transgenic AD mice, indicating that JNK plays an important role in the hyperphosphorylation of tau protein [16].
In short, these findings from cells and animal models fully indicate that the JNK signaling pathway plays an indispensable role in the pathogenesis of neurodegenerative diseases; therefore, JNK is likely to be a potential therapeutic target for neurodegenerative diseases.
JNK regulates the pathogenesis of neurodegenerative diseases (picture quoted from: Zhao et al.
Alzheimer's & Dementia2021; 1-7) Hypothesis verification In this article, the team proposed that large animals with greater genetic homology to humans ( Such as chimpanzees, pigs, etc.
) are used to verify the hypothesis that JNK is a potential therapeutic target for neurodegenerative diseases. For example, p-JNK, phosphorylated JNK, can be injected into the cerebral cortex of an elderly chimpanzee (chimpanzee) to observe whether there are pathological features of neurodegenerative diseases.
It is worth noting that due to the slow onset of symptoms of neurodegenerative diseases, this study should be conducted for a long time.
Unfortunately, the direct injection of p-JNK will not only cause local penetrating damage to the brain tissue, but also cause local accumulation of large doses.
In order to solve these limitations, the team also proposed that CRISPR technology can be used to build genetically modified pig or chimpanzee models to further verify the proposed hypothesis.
Challenges Currently, elucidating the mechanism of action of JNK in neurodegenerative diseases mainly depends on cells and rodent models (mouse or rat).
However, the short life span of rodents, the evolutionary isolation and anatomical heterogeneity of rodents are the limiting factors for its use as animal models for research, and inbred animals cannot truly mimic the diversity of human genes.
In the genome, rodents and humans have only 48-66% genetic homology, while non-human primates, such as chimpanzees, have more than 80% genetic homology with humans [17].
Therefore, the establishment of large animal models will be a better choice.
It is worth noting that although non-human primate animal models can be used as an alternative to more realistically reproduce the human disease process, their construction is time-consuming, expensive, and requires additional in vitro tests for verification.
These in vitro tests usually use rodent nerve cells.
Because older nerve cells cannot survive in the culture medium, the pathological development of neurodegenerative diseases cannot be observed.
Conclusions and prospects For the future, JNK3 will be an important target and biomarker for the treatment of neurodegenerative diseases.
At the same time, because glial cells participate in many important physiological and pathological processes of the brain, the role of JNK3 in glial cells should be further studied.
Since the incidence of many neurodegenerative diseases is related to gender, whether the activation of JNK3 is related to gender remains to be further studied.
In addition, the underlying mechanism of how JNK affects synaptic dysfunction still needs to be further revealed.
In this article, graduate student Zhao Yingying of Yangtze University and Professor Kamil Kuca of Hradec Králové University in the Czech Republic are the co-first authors; Professor Wu Qinghua of Yangtze University is the only corresponding author of this article.
Zhao Yingying (left), Kamil Kuca (middle), Wu Qinghua (right) (picture source: Wu Qinghua Laboratory of Yangtze University) Original link: https://alz-journals.
onlinelibrary.
wiley.
com/doi/10.
1002/alz.
12370 reference Literature (slide up and down to view) 【1】Goedert M.
Alzheimer's and Parkinson's diseases: The prion concept in relation to assembled Abeta, tau, and alpha-synuclein.
Science.
2015;349:1255555.
【2】Yarza R, Vela S, Solas M, Ramirez MJ.
c-Jun N-terminal Kinase (JNK) signaling as a therapeutic target for Alzheimer's Disease.
Front Pharmacol.
2015;6:321.
[3] Musi CA, Agro G, Santarella F, Iervasi E, Borsello T.
JNK3 as Therapeutic Target and Biomarker in Neurodegenerative and Neurodevelopmental Brain Diseases.
Cells.
2020;9:2190.
[4] Antoniou X, Falconi M, Di Marino D, Borsello T.
JNK3 as a therapeutic target for neurodegenerative diseases.
J Alzheimers Dis.
2011;24:633-42.
[5] Komulainen E, Varidaki A, Kulesskaya N, Mohammad H, Sourander C, Rauvala H,et al.
Impact of JNK and Its Substrates on Dendritic Spine Morphology.
Cells.
2020;9:440.
[6] Yoshida H, Hastie CJ, McLauchlan H, Cohen P, Goedert M.
Phosphorylation of microtubule-associated protein tau by isoforms of c-Jun N-terminal kinase (JNK).
J Neurochem.
2004;90:352-8.
[7] Yoon SO, Park DJ, Ryu JC, Ozer HG, Tep C, Shin YJ, et al.
JNK3 perpetuates metabolic stress induced by Abeta peptides.
Neuron.
2012;75:824-37.
【8】Kim EK, Choi EJ.
Pathological roles of MAPK signaling pathways in human diseases.
Biochim Biophys Acta.
2010;1802:396-405.
【9】Zhang X, Tang S, Zhang Q, Shao W, Han X, Wang Y, et al.
Endoplasmic reticulum stress mediates JNK-dependent IRS-1 serine phosphorylation and results in Tau hyperphosphorylation in amyloid beta oligomer-treated PC12 cells and primary neurons.
Gene .
2016;587:183-93.
【10】Vogel J, Anand VS, Ludwig B, Nawoschik S,Dunlop J, Braithwaite SP.
The JNK pathway amplifies and drives subcellular changes in tau phosphorylation.
Neuropharmacology.
2009;57:539-50.
[11] Hunot S, Vila M, Teismann P, Davis RJ, Hirsch EC, Przedborski S, et al.
JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease.
Proc Natl Acad Sci US A.
2004;101:665-70.
【12】Sherrin T, Blank T, Todorovic C.
c- Jun N-terminal kinases in memory and synaptic plasticity.
Rev Neurosci.
2011;22:403-10.
[13] de Lemos L, Junyent F, Camins A, Castro-Torres RD, Folch J, Olloquequi J, et al.
Neuroprotective effects of the absence of JNK1 or JNK3 isoforms on kainic acid-induced temporal lobe epilepsy-like symptoms.
Mol Neurobiol.
2018;55:4437-52.
[14] Yao M, Nguyen TV, Pike CJ.
Beta-amyloid-induced neuronal apoptosis involves c-Jun N-terminal kinase-dependent downregulation of Bcl-w.
J Neurosci.
2005;25:1149-58.
[15] Colombo A, Bastone A, Ploia C, Sclip A, Salmona M, Forloni G, et al.
JNK regulates APP cleavage and degradation in a model of Alzheimer's disease.
Neurobiol Dis.
2009;33:518-25.
[16] Ploia C, Antoniou X, Sclip A, Grande V, Cardinetti D, Colombo A, et al.
JNK plays a key role in tau hyperphosphorylation in Alzheimer's disease models.
J Alzheimers Dis.
2011;26:315-29.
[17] Eaton SL, Wishart TM.
Bridging the gap: large animal models in neurodegenerative research .
Mamm Genome.
2017;28:324-37.
Plate making ︱ Wang Sizhen End of this articleJNK regulates APP cleavage and degradation in a model of Alzheimer's disease.
Neurobiol Dis.
2009;33:518-25.
[16] Ploia C, Antoniou X, Sclip A, Grande V, Cardinetti D, Colombo A, et al.
JNK plays a key role in tau hyperphosphorylation in Alzheimer's disease models.
J Alzheimers Dis.
2011;26:315-29.
【17】Eaton SL, Wishart TM.
Bridging the gap: large animal models in neurodegenerative research.
Mamm Genome.
2017;28: 324-37.
Plate Making︱Wang Sizhen End of this articleJNK regulates APP cleavage and degradation in a model of Alzheimer's disease.
Neurobiol Dis.
2009;33:518-25.
[16] Ploia C, Antoniou X, Sclip A, Grande V, Cardinetti D, Colombo A, et al.
JNK plays a key role in tau hyperphosphorylation in Alzheimer's disease models.
J Alzheimers Dis.
2011;26:315-29.
【17】Eaton SL, Wishart TM.
Bridging the gap: large animal models in neurodegenerative research.
Mamm Genome.
2017;28: 324-37.
Plate Making︱Wang Sizhen End of this article
Such diseases are caused by the loss of neurons and/or their myelin sheaths, which worsen over time, leading to neurological dysfunction [1].
Due to the multiple factors and complexity of the etiology of these diseases, there is still no best treatment drug.
In the past 20 years, scientists have done a lot of research on the pathogenesis of neurodegenerative diseases, and new mechanisms have been continuously reported.
Studies have found that tau protein hyperphosphorylation, β-amyloid (Aβ) deposition, acetylcholine deficiency, synapse loss, dendritic pruning, etc.
are closely related to neurodegenerative diseases [2-3].
However, the master switch that regulates these complex mechanisms, that is, the upstream regulatory signal protein, is still unclear, so that there has been no major breakthrough in the treatment of neurodegenerative diseases by target molecules.
On May 25, 2021, the team of Professor Wu Qinghua and Professor Kamil Kuca from the Joint Laboratory of Toxicology of Yangtze University-Hradec Kralove University (Czech Republic) published an online publication entitled "Hypothesis: JNK Signaling is" in Alzheimer's & Dementia.
a Therapeutic Target of Neurodegenerative Diseases" Scientific Hypothesis Article (Review Article).
Based on a large amount of data from cell and animal experiments, the team comprehensively analyzed the mechanism of JNK signaling in the pathogenesis of neurodegenerative diseases, and put forward the hypothesis: JNK is a potential target for the treatment of neurodegenerative diseases.
This article provides an in-depth analysis of how to effectively verify this scientific hypothesis and the challenges it faces.
This hypothesis provides new ideas for the development of Alzheimer's disease target drugs and precision molecular treatment of such diseases.
Background JNK, also known as stress-activated protein kinase, is another subtype of MAPK (mitogen-activated protein kinase) signaling pathway in mammalian cells.
JNK protein kinase is encoded by three genes.
The JNK1 and JNK2 genes are widely expressed throughout the body, while the JNK3 gene is mainly expressed in the brain and less expressed in the heart and testis [4].
JNK1/2 is involved in the regulation of immune cells and the development of the embryonic nervous system, while JNK3 is the main subtype activated by stress stimulation and is mainly involved in the process of neurodegeneration [3,5].
Studies have shown that the activation of JNK is not only related to the hyperphosphorylation of tau protein in AD and other neurodegenerative diseases, but also involved in the production and accumulation of Aβ [6-8].
JNK can phosphorylate tau protein at multiple sites and cause it to dissociate from microtubules, which ultimately leads to the formation of neurofibrillary tangles [6,9].
Among them, JNK3 can strongly autophosphorylate and promote tau hyperphosphorylation [10].
It is worth noting that JNK3 promotes the production of Aβ42, the main component of senile plaques, through phosphorylation of amyloid precursor protein (APP); in turn, Aβ can induce JNK activation, thereby forming a positive feedback loop [7-8].
The JNK signaling pathway is also related to the progressive loss of dopaminergic neurons in the substantia nigra, which is the main cause of PD [11].
In addition, the physiologically active JNK modulates synaptic strength and promotes synaptic plasticity through phosphorylation of different substrates [4].
Although the basal level of JNK activity is necessary for inducing synaptic plasticity, overactivation of JNK induced by stress is harmful to synaptic plasticity and may lead to memory defects and neurodegeneration [5,12].
The mechanism of JNK in the formation of neurofibrillary tangles (picture quoted from: Zhao et al.
Alzheimer's & Dementia2021; 1-7) hypothesis that the JNK signaling pathway affects the function of neurons, leading to nerve damage and subsequent spatial learning And memory impairment.
For example, treatment of JNK3 knockout mice with the glutamate receptor agonist kainic acid found that the degeneration of hippocampal neurons in the mice was reduced [13].
In addition, treatment of primary rat cortical neurons with JNK inhibitors can effectively prevent the down-regulation of the anti-apoptotic proteins Bcl-w and Bcl-xL, indicating that JNK is involved in the neuronal death pathway [14].
The memory of JNK1 gene-deficient mice and the spinous structure of hippocampal neuron dendrites have been destroyed, indicating that JNK is essential in synaptic plasticity [5].
However, continuous activation of JNK is harmful to synaptic plasticity [12].
In addition, it was found in the H4-APPsw cell line that inhibition of JNK activity can prevent the phosphorylation of APP at Thr 668, thereby greatly reducing Aβ fragments; this fully proves that JNK participates in the phosphorylation of APP at Thr668.
This promotes the production of Aβ protein [15].
Similarly, the inhibition of JNK can also prevent the phosphorylation of tau in rat cortical neurons and transgenic AD mice, indicating that JNK plays an important role in the hyperphosphorylation of tau protein [16].
In short, these findings from cells and animal models fully indicate that the JNK signaling pathway plays an indispensable role in the pathogenesis of neurodegenerative diseases; therefore, JNK is likely to be a potential therapeutic target for neurodegenerative diseases.
JNK regulates the pathogenesis of neurodegenerative diseases (picture quoted from: Zhao et al.
Alzheimer's & Dementia2021; 1-7) Hypothesis verification In this article, the team proposed that large animals with greater genetic homology to humans ( Such as chimpanzees, pigs, etc.
) are used to verify the hypothesis that JNK is a potential therapeutic target for neurodegenerative diseases. For example, p-JNK, phosphorylated JNK, can be injected into the cerebral cortex of an elderly chimpanzee (chimpanzee) to observe whether there are pathological features of neurodegenerative diseases.
It is worth noting that due to the slow onset of symptoms of neurodegenerative diseases, this study should be conducted for a long time.
Unfortunately, the direct injection of p-JNK will not only cause local penetrating damage to the brain tissue, but also cause local accumulation of large doses.
In order to solve these limitations, the team also proposed that CRISPR technology can be used to build genetically modified pig or chimpanzee models to further verify the proposed hypothesis.
Challenges Currently, elucidating the mechanism of action of JNK in neurodegenerative diseases mainly depends on cells and rodent models (mouse or rat).
However, the short life span of rodents, the evolutionary isolation and anatomical heterogeneity of rodents are the limiting factors for its use as animal models for research, and inbred animals cannot truly mimic the diversity of human genes.
In the genome, rodents and humans have only 48-66% genetic homology, while non-human primates, such as chimpanzees, have more than 80% genetic homology with humans [17].
Therefore, the establishment of large animal models will be a better choice.
It is worth noting that although non-human primate animal models can be used as an alternative to more realistically reproduce the human disease process, their construction is time-consuming, expensive, and requires additional in vitro tests for verification.
These in vitro tests usually use rodent nerve cells.
Because older nerve cells cannot survive in the culture medium, the pathological development of neurodegenerative diseases cannot be observed.
Conclusions and prospects For the future, JNK3 will be an important target and biomarker for the treatment of neurodegenerative diseases.
At the same time, because glial cells participate in many important physiological and pathological processes of the brain, the role of JNK3 in glial cells should be further studied.
Since the incidence of many neurodegenerative diseases is related to gender, whether the activation of JNK3 is related to gender remains to be further studied.
In addition, the underlying mechanism of how JNK affects synaptic dysfunction still needs to be further revealed.
In this article, graduate student Zhao Yingying of Yangtze University and Professor Kamil Kuca of Hradec Králové University in the Czech Republic are the co-first authors; Professor Wu Qinghua of Yangtze University is the only corresponding author of this article.
Zhao Yingying (left), Kamil Kuca (middle), Wu Qinghua (right) (picture source: Wu Qinghua Laboratory of Yangtze University) Original link: https://alz-journals.
onlinelibrary.
wiley.
com/doi/10.
1002/alz.
12370 reference Literature (slide up and down to view) 【1】Goedert M.
Alzheimer's and Parkinson's diseases: The prion concept in relation to assembled Abeta, tau, and alpha-synuclein.
Science.
2015;349:1255555.
【2】Yarza R, Vela S, Solas M, Ramirez MJ.
c-Jun N-terminal Kinase (JNK) signaling as a therapeutic target for Alzheimer's Disease.
Front Pharmacol.
2015;6:321.
[3] Musi CA, Agro G, Santarella F, Iervasi E, Borsello T.
JNK3 as Therapeutic Target and Biomarker in Neurodegenerative and Neurodevelopmental Brain Diseases.
Cells.
2020;9:2190.
[4] Antoniou X, Falconi M, Di Marino D, Borsello T.
JNK3 as a therapeutic target for neurodegenerative diseases.
J Alzheimers Dis.
2011;24:633-42.
[5] Komulainen E, Varidaki A, Kulesskaya N, Mohammad H, Sourander C, Rauvala H,et al.
Impact of JNK and Its Substrates on Dendritic Spine Morphology.
Cells.
2020;9:440.
[6] Yoshida H, Hastie CJ, McLauchlan H, Cohen P, Goedert M.
Phosphorylation of microtubule-associated protein tau by isoforms of c-Jun N-terminal kinase (JNK).
J Neurochem.
2004;90:352-8.
[7] Yoon SO, Park DJ, Ryu JC, Ozer HG, Tep C, Shin YJ, et al.
JNK3 perpetuates metabolic stress induced by Abeta peptides.
Neuron.
2012;75:824-37.
【8】Kim EK, Choi EJ.
Pathological roles of MAPK signaling pathways in human diseases.
Biochim Biophys Acta.
2010;1802:396-405.
【9】Zhang X, Tang S, Zhang Q, Shao W, Han X, Wang Y, et al.
Endoplasmic reticulum stress mediates JNK-dependent IRS-1 serine phosphorylation and results in Tau hyperphosphorylation in amyloid beta oligomer-treated PC12 cells and primary neurons.
Gene .
2016;587:183-93.
【10】Vogel J, Anand VS, Ludwig B, Nawoschik S,Dunlop J, Braithwaite SP.
The JNK pathway amplifies and drives subcellular changes in tau phosphorylation.
Neuropharmacology.
2009;57:539-50.
[11] Hunot S, Vila M, Teismann P, Davis RJ, Hirsch EC, Przedborski S, et al.
JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease.
Proc Natl Acad Sci US A.
2004;101:665-70.
【12】Sherrin T, Blank T, Todorovic C.
c- Jun N-terminal kinases in memory and synaptic plasticity.
Rev Neurosci.
2011;22:403-10.
[13] de Lemos L, Junyent F, Camins A, Castro-Torres RD, Folch J, Olloquequi J, et al.
Neuroprotective effects of the absence of JNK1 or JNK3 isoforms on kainic acid-induced temporal lobe epilepsy-like symptoms.
Mol Neurobiol.
2018;55:4437-52.
[14] Yao M, Nguyen TV, Pike CJ.
Beta-amyloid-induced neuronal apoptosis involves c-Jun N-terminal kinase-dependent downregulation of Bcl-w.
J Neurosci.
2005;25:1149-58.
[15] Colombo A, Bastone A, Ploia C, Sclip A, Salmona M, Forloni G, et al.
JNK regulates APP cleavage and degradation in a model of Alzheimer's disease.
Neurobiol Dis.
2009;33:518-25.
[16] Ploia C, Antoniou X, Sclip A, Grande V, Cardinetti D, Colombo A, et al.
JNK plays a key role in tau hyperphosphorylation in Alzheimer's disease models.
J Alzheimers Dis.
2011;26:315-29.
[17] Eaton SL, Wishart TM.
Bridging the gap: large animal models in neurodegenerative research .
Mamm Genome.
2017;28:324-37.
Plate making ︱ Wang Sizhen End of this articleJNK regulates APP cleavage and degradation in a model of Alzheimer's disease.
Neurobiol Dis.
2009;33:518-25.
[16] Ploia C, Antoniou X, Sclip A, Grande V, Cardinetti D, Colombo A, et al.
JNK plays a key role in tau hyperphosphorylation in Alzheimer's disease models.
J Alzheimers Dis.
2011;26:315-29.
【17】Eaton SL, Wishart TM.
Bridging the gap: large animal models in neurodegenerative research.
Mamm Genome.
2017;28: 324-37.
Plate Making︱Wang Sizhen End of this articleJNK regulates APP cleavage and degradation in a model of Alzheimer's disease.
Neurobiol Dis.
2009;33:518-25.
[16] Ploia C, Antoniou X, Sclip A, Grande V, Cardinetti D, Colombo A, et al.
JNK plays a key role in tau hyperphosphorylation in Alzheimer's disease models.
J Alzheimers Dis.
2011;26:315-29.
【17】Eaton SL, Wishart TM.
Bridging the gap: large animal models in neurodegenerative research.
Mamm Genome.
2017;28: 324-37.
Plate Making︱Wang Sizhen End of this article
