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

Colombo, Alessio; Repici, Mariaelena; Pesaresi, Marzia; Santambrogio, Sara; Forloni, Gianluigi; Borsello, Tiziana

doi:10.1038/sj.cdd.4402202

Cited by 42 publications

(28 citation statements)

References 18 publications

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“…Recent data have supported the notion that JNK activation is associated with tauinduced neurodegeneration (Yoshida et al 2004;Lagalwar et al 2006;Dias-Santagata et al 2007) and with Aβ pathology (Hashimoto et al 2003;Colombo et al 2007). Furthermore, JNKs were involved in Aβ triggered down regulation of the anti-apoptotic Bcl-w (Yao et al 2005) and activation of Toll-like receptor 4 (TLR4) signaling.…”

Section: In Admentioning

confidence: 87%

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JNK: A Stress-Activated Protein Kinase Therapeutic Strategies and Involvement in Alzheimer’s and Various Neurodegenerative Abnormalities

Mehan¹,

Meena²,

Sharma³

et al. 2010

J Mol Neurosci

150

102

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The c-Jun N-terminal kinase (JNKs), also known as stress-activated protein kinase (SAPK), is one such family of multifunctional-signaling molecules, activated in response to wide range of cellular stresses as well as in response to inflammatory mediators. JNKs regulate various processes such as brain development, repair, and memory formation; but on the other hand, JNKs are potent effectors of neuroinflammation and neuronal death. A large body of evidence indicates that JNK activity is critical for normal immune and inflammatory response. Indeed, aberrant activation of JNK has been implicated in the pathogenesis of Alzheimer's disease. Moreover, the JNK pathway is considered to be a key regulator of various inflammatory pathways which are activated during normal aging and Alzheimer's disease therapy as well as key regulator of pro-inflammatory cytokines biosynthesis at the transcriptional and translational levels, which makes different components of these pathway potential targets for the treatment of autoimmune and inflammatory diseases. Pharmacological inhibition of JNK has been demonstrated to attenuate microglial activation and the release of neurotoxic chemicals including pro-inflammatory cytokines. In this review, we provide an overview on implications and therapeutic strategies of JNK in neurodegenerative disorders.

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Section: In Admentioning

confidence: 87%

“…Neurons from TLR4 mutant mice exhibit reduced JNK and caspase-3 activation and are protected against Aβ induced apoptosis (Tang et al 2008). Similarly, the D-JNK1-I peptide inhibitor could efficiently diminish the production of Aβ precursor protein and Aβ fragments (Colombo et al 2007). …”

Section: In Admentioning

confidence: 97%

JNK: A Stress-Activated Protein Kinase Therapeutic Strategies and Involvement in Alzheimer’s and Various Neurodegenerative Abnormalities

Mehan¹,

Meena²,

Sharma³

et al. 2010

J Mol Neurosci

150

102

View full text Add to dashboard Cite

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“…Potential neuroprotective peptides fused to CPPs have been assessed in cultured neurons and animal models that mimic neural injury mechanisms seen in a variety of disorders, including cerebral ischaemia, spinal cord injury, traumatic brain injury, epilepsy, Parkinson's disease and Alzheimer's disease (Arthur et al, 2007;Colombo et al, 2007;Lai et al, 2005;Liu et al, 2006;Meade et al, 2009;Nagel et al, 2008). However, several years ago, we and others demonstrated that TAT possesses intrinsic neuroprotective properties both in vitro in neurons exposed to excitotoxicity and oxygen-glucose deprivation (OGD) and in vivo following cerebral ischaemia in P12 rats after intraventricular injection (Craig et al, 2011;Meade et al, 2010a, b;Vaslin et al, 2009b;Xu et al, 2008).…”

Section: Arginine-rich Cell Penetrating Peptides and Intrinsic Neuropmentioning

confidence: 99%

Neuroprotective peptides fused to arginine-rich cell penetrating peptides: Neuroprotective mechanism likely mediated by peptide endocytic properties

Meloni

Milani

Edwards

et al. 2015

Pharmacology & Therapeutics

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Several recent studies have demonstrated that TAT and other arginine-rich cell penetrating peptides (CPPs) have intrinsic neuroprotective properties in their own right. Examples, we have demonstrated that in addition to TAT, poly-arginine peptides (R8 to R18; containing 8-18 arginine residues) as well as some other arginine-rich peptides are neuroprotective in vitro (in neurons exposed to glutamic acid excitotoxicity and oxygen glucose deprivation) and in the case of R9 in vivo (after permanent middle cerebral artery occlusion in the rat). Based on several lines of evidence, we propose that this neuroprotection is related to the peptide's endocytosis-inducing properties, with peptide charge and arginine residues being critical factors. Specifically, we propose that during peptide endocytosis neuronal cell surface structures such as ion channels and transporters are internalised, thereby reducing calcium influx associated with excitotoxicity and other receptor-mediated neurodamaging signalling pathways. We also hypothesise that a peptide cargo can act synergistically with TAT and other arginine-rich CPPs due to potentiation of the CPPs endocytic traits rather than by the cargo-peptide acting directly on its supposedly intended intracellular target. In this review, we systematically consider a number of studies that have used CPPs to deliver neuroprotective peptides to the central nervous system (CNS) following stroke and other neurological disorders. Consequently, we critically review evidence that supports our hypothesis that neuroprotection is mediated by carrier peptide endocytosis. In conclusion, we believe that there are strong grounds to regard arginine-rich peptides as a new class of neuroprotective molecules for the treatment of a range of neurological disorders.

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“…JNK activation has been reported to regulate the phosphorylation of APP, leading to modulation of Ab levels (Colombo et al 2007;Colombo et al 2009), as well as to mediate the phosphorylation of tau protein in vitro (Yoshida et al 2004). Furthermore, the JNK pathway is shown activated in preclinical models of AD, including Tg2576 and Tg575/PS1 P264L transgenic mice (Flood et al 2002;Puig et al 2004), as well as in brains of AD patients (Zhu et al 2003a;Zhu et al 2003b;Lagalwar et al 2006).…”

Section: Ab Production Is a Major Link Between Oxidative Stress And Pmentioning

confidence: 99%

Amyloid-β Production: Major Link Between Oxidative Stress and BACE1

et al. 2011

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Sequential endoproteolytic cleavages operated by the c-secretase and the b-secretase (BACE1) on the b-amyloid precursor protein result in the production of the b-amyloid (Ab) species, with two C-terminal variants, at residue 40 or at residue 42. Accumulation in brain tissue of aggregates of Ab42 is the major pathogenetic event in Alzheimer's disease (AD). The causes of Ab accumulation in the common sporadic form of AD are not completely understood, but they are likely to include oxidative stress (OS). Data reviewed here shed light on how Ab generation, oxidative stress, and secretase functions are intimately related in sporadic AD. According to our hypothesis, in sporadic AD, OS resulted from several cellular insults such as aging, hypoxia, hyperglycemia, and hypercholesterolemia-that are well-known risk factors for AD development-can determine a primary induction of c-secretase and BACE1. The loop proceeds with the generation of Ab42 and its signaling to BACE1 transcription.

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

Cited by 42 publications

References 18 publications

JNK: A Stress-Activated Protein Kinase Therapeutic Strategies and Involvement in Alzheimer’s and Various Neurodegenerative Abnormalities

JNK: A Stress-Activated Protein Kinase Therapeutic Strategies and Involvement in Alzheimer’s and Various Neurodegenerative Abnormalities

Neuroprotective peptides fused to arginine-rich cell penetrating peptides: Neuroprotective mechanism likely mediated by peptide endocytic properties

Amyloid-β Production: Major Link Between Oxidative Stress and BACE1

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