Increased levels of cerebrospinal fluid JNK3 associated with amyloid pathology: links to cognitive decline

Gourmaud, Sarah; Paquet, Claire; Dumurgier, Julien; Pace, Clarisse; Bouras, Constantin; Gray, Françoise; Laplanche, Jean‐Louis; Meurs, Éliane; Mouton-Liger, François; Hugon, Jacques

doi:10.1503/jpn.140062

Cited by 83 publications

(72 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…P‐JNK staining is found to localize in neurons surrounding amyloid plaques and in neurons that contained intracellular accumulations of Aβ both in patients with AD and in AD mouse models (Shoji et al ., 2000; Zhu et al ., 2001). The levels of JNK3 and p‐JNK are also increased in cerebrospinal fluid (CSF) and are correlated with the rate of cognitive decline in patients with AD (Gourmaud et al ., 2015). In primary hippocampal neurons, the levels of active JNK and phosphorylated IRS1 (Ser616) and tau (Ser422) are significantly increased by exposure to Aβ oligomers (Shoji et al ., 2000).…”

Section: Discussionmentioning

confidence: 99%

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

et al. 2016

View full text Add to dashboard Cite

SummaryBrain insulin signaling deficits contribute to multiple pathological features of Alzheimer's disease (AD). Although intranasal insulin has shown efficacy in patients with AD, the underlying mechanisms remain largely unillustrated. Here, we demonstrate that intranasal insulin improves cognitive deficits, ameliorates defective brain insulin signaling, and strongly reduces β‐amyloid (Aβ) production and plaque formation after 6 weeks of treatment in 4.5‐month‐old APPswe/PS1dE9 (APP/PS1) mice. Furthermore, c‐Jun N‐terminal kinase activation, which plays a pivotal role in insulin resistance and AD pathologies, is significantly inhibited. The alleviation of amyloid pathology by intranasal insulin results mainly from enhanced nonamyloidogenic processing and compromised amyloidogenic processing of amyloid precursor protein (APP), and from a reduction in apolipoprotein E protein which is involved in Aβ metabolism. In addition, intranasal insulin effectively promotes hippocampal neurogenesis in APP/PS1 mice. This study, exploring the mechanisms underlying the beneficial effects of intranasal insulin on Aβ pathologies in vivo for the first time, highlights important preclinical evidence that intranasal insulin is potentially an effective therapeutic method for the prevention and treatment of AD.

show abstract

Section: Discussionmentioning

confidence: 99%

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Critical in this inflammatory response is the activation of downstream cellular stress pathways with JNK and IKK being the most involved. JNK is the major intracellular kinase mediating TNF-a inhibitory phosphorylation of IRS-1 in T2DM [82,83], and it was found to be activated in obesity [84], in postmortem AD brain tissue and CSF [85]. Moreover, pJNK is elevated in a transgenic mouse model of AD [86] and in cynomolgus monkeys after ICV injection of oligomeric Ab [63].…”

Section: Inflammation As a Link Between Insulin Dysregulation In Metamentioning

confidence: 99%

Insulin signalling in Alzheimer′s disease and diabetes: from epidemiology to molecular links

Ribé

Lovestone

2016

J Intern Med

View full text Add to dashboard Cite

Abstract. Ribe EM, Lovestone S (University of Oxford, Oxford, UK). Insulin signalling in Alzheimer 0 s disease and diabetes: from epidemiology to molecular links (Key Symposium). J Intern Med 2016; 280: 430-442.As populations across the world both age and become more obese, the numbers of individuals with Alzheimer 0 s disease and diabetes are increasing; posing enormous challenges for society and consequently becoming priorities for governments and global organizations. These issues, an ageing population at risk of neurodegenerative diseases such as Alzheimer 0 s disease and an increasingly obese population at risk of metabolic alterations such as type 2 diabetes, are usually considered as independent conditions, but increasing evidence from both epidemiological and molecular studies link these disorders. The aim of this review was to highlight these multifactorial links. We will discuss the impact of direct links between insulin and IGF-1 signalling and the Alzheimer 0 s disease-associated pathological events as well as the impact of other processes such as inflammation, oxidative stress and mitochondrial dysfunction either common to both conditions or perhaps responsible for a mechanistic link between metabolic and neurodegenerative disease. An understanding of such associations might be of importance not only in the understanding of disease mechanisms but also in the search for novel therapeutic options.

show abstract

“…JNK3 is a MAP-kinase which is specifically expressed in the central nervous system (CNS) where it becomes up-regulated after traumatic brain injury (73,74). Within the CNS, it may be expressed in neurons, oligodendrocytes, and astrocytes (75)(76)(77). JNK inhibition in an Alzheimer's disease (AD) model partially restored synaptic dysfunctions (78) which are of particular interest with regard to the SMA pathology.…”

Section: Intervention In Cellular Signaling As a Strategy For Smn-indmentioning

confidence: 99%

The Need for SMN-Independent Treatments of Spinal Muscular Atrophy (SMA) to Complement SMN-Enhancing Drugs

2020

View full text Add to dashboard Cite

Spinal Muscular Atrophy (SMA) is monogenic motoneuron disease caused by low levels of the Survival of Motoneuron protein (SMN). Recently, two different drugs were approved for the treatment of the disease. The antisense oligonucleotide Nusinersen/Spinraza ® and the gene replacement therapy Onasemnogene Abeparvovec/Zolgensma ® both enhance SMN levels. These treatments result in impressive benefits for the patients. However, there is a significant number of non-responders and an intervention delay has a strong negative impact on the efficacy. Obviously, later stages of motoneuron degeneration cannot be reversed by SMN-restoration. Therefore, complementary, SMN-independent strategies are needed which are able to address such SMN-irreversible degenerative processes. Those are defined as pathological alterations which are not reversed by SMN-restoration for a given dose and intervention delay. It is crucial to tailor SMN-independent approaches to the novel clinical situation with SMN-restoring treatments. On the molecular level, such SMN-irreversible changes become manifest in altered signaling modules as described by molecular systems biology. Based on our current knowledge about altered signaling, we introduce a network approach for an informed decision for the most potent SMN-independent treatment targets. Finally, we present recommendations for the identification of novel treatments which can be combined with SMN-restoring drugs.

show abstract

Increased levels of cerebrospinal fluid JNK3 associated with amyloid pathology: links to cognitive decline

Cited by 83 publications

References 49 publications

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

Insulin signalling in Alzheimer′s disease and diabetes: from epidemiology to molecular links

The Need for SMN-Independent Treatments of Spinal Muscular Atrophy (SMA) to Complement SMN-Enhancing Drugs

Contact Info

Product

Resources

About