NAP (davunetide) modifies disease progression in a mouse model of severe neurodegeneration: Protection against impairments in axonal transport

Jouroukhin, Yan; Ostritsky, Regina; Assaf, Yaniv; Pelled, Galit; Giladi, Eliezer; Gozes, Illana

doi:10.1016/j.nbd.2013.04.012

Cited by 101 publications

(89 citation statements)

References 108 publications

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“…Experimental fi ndings from this study showed that the NAP-containing peptides increased microtubule density, yet decreased β-tubulin, thus suggesting that these peptides may play a role in regulating the composition of microtubule-stabilizing isoforms [116,117] . Administration of NAP induces cognitive improvement in an AD mouse model, protects microtubules in a Parkinson model, and has neuroprotective effect in an amyotrophic lateral sclerosis model [118,119] .Heavy emphasis has been placed on understanding what other potential natural treatment types could be investigated [120] . It has been shown that turmeric extract has anti-amyloidogenic properties [121] .…”

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confidence: 99%

Tau-induced neurodegeneration: mechanisms and targets

Beharry

Cohen

et al. 2014

Neurosci. Bull.

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The accumulation of hyperphosphorylated tau is a common feature of several dementias. Tau is one of the brain microtubule-associated proteins. Here we discuss tau's functions in microtubule assembly and stabilization and with regard to its interactions with other proteins. We describe and analyze important post-translational modifications: hyperphosphorylation, ubiquitination, glycation, glycosylation, nitration, polyamination, proteolysis, acetylation, and methylation. We discuss how these post-translational modifi cations can alter tau's biological function. We analyze the role of mitochondrial health in neurodegeneration. We propose that microtubules could be a therapeutic target and review different approaches. Finally, we consider whether tau accumulation or its conformational change is related to tau-induced neurodegeneration, and propose a mechanism of neurodegeneration.Keywords: tau; phosphorylation; neurodegeneration; tauopathies; mitochondria; microtubules; tubulin; kinases; phosphatases; Alzheimer's disease ·Review· IntroductionAlzheimer 's disease (AD), first described by Alois Alzheimer more than 100 years ago [1] , is a progressive neurodegenerative disorder, characterized by an insidious onset with irreversible cognitive declines that lead to profound mental deterioration causing dementia [2] . Two major forms of lesion characterize AD: amyloid as diffuse neurotic plaques primarily composed of the Aβ peptide [3] , which are mainly insoluble deposits of protein and cellular material, and neurofibrillary tangles composed of fi lamentous hyperphosphorylated tau protein that builds up inside the neuron [4,5] .Amyloid precursor protein (APP) is a highly conserved transmembrane protein [6] believed to play a role in synapse formation, synaptic plasticity, and neuronal survival [7][8][9] .In AD, APP is cleaved by β-and γ-secretases leading to the overproduction of an abnormal proteolytic byproduct called amyloid beta (Aβ) [10] . Upon cleavage fragments of Aβ of various sizes are released from the membrane and aggregate in the brain to form the characteristic plaques seen in AD. Plaques are composed primarily of the 40 and 42 amino-acid peptide fragments Aβ40 and Aβ42, the latter being the predominant species. In addition, Aβ42 is more prone to aggregation and deposition and therefore the cause of neurotoxicity, as well as synaptic loss [11] .The second lesion in AD is formed by aggregates of the microtubule-associated protein tau, which forms intracytoplasmic neuronal inclusions or neurofibrillary tangles when hyperphosphorylated [12] . Tau is associated with neurons of the central nervous system [13] and its main biological function is promoting the in vitro assembly and stabilization of microtubules in the cytoskeleton [14,15] . Tau is a phosphoprotein that is encoded by a single gene, MAPT, located on chromosome 17q21 [16] ; alternative splicing of the gene produces six major isoforms expressed in the adult human brain [17] . Isoforms derive their names from the number of microtubule-binding repeat s...

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confidence: 99%

Tau-induced neurodegeneration: mechanisms and targets

Beharry

Cohen

et al. 2014

Neurosci. Bull.

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“…Thus, NAP protects MTs and the autophagy process (Esteves et al 2014) inhibiting apoptosis. Importantly, NAP protects MT-dependent axonal transport (Jouroukhin et al 2013;Quraishe et al 2013), with postmortem AD brains showing depletion in MTs (Cash et al 2003). Capitulating on the NAP target, we have designed SKIP (Ser-Lys-Ile-Pro) and shown that it mimics NAP protection, as well as protects ADNP-deficient impairment in axonal transport (Amram et al 2016).…”

Section: Mechanism and Future Horizonsmentioning

confidence: 99%

Microtubule-Tau Interaction as a Therapeutic Target for Alzheimer’s Disease

et al. 2016

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“…To improve the permeability of the BBB, new generation compounds such as BMS-241027 have been synthesized and shown to benefit tau mice and it is now undergoing Phase 1 clinical trials [226]. In addition to taxol derivatives (paclitaxel, BMS-241027, TPI-287), neuroprotective peptides such as Davunetide (NAP) can also protect MT in tauopathies [227,228]. NAP has been evaluated in a Phase II/III clinical trial, but was reported to have failed in progressive supranuclear palsy (PSP) treatment [229,230].…”

Section: Microtubule Stabilizationmentioning

confidence: 99%

Behind the curtain of tauopathy: a show of multiple players orchestrating tau toxicity

Huang

Zhou

2015

Cell. Mol. Life Sci.

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tau, a microtubule-associated protein, directly binds with microtubules to dynamically regulate the organization of cellular cytoskeletons, and is especially abundant in neurons of the central nervous system. Under disease conditions such as Pick's disease, progressive supranuclear palsy, frontotemporal dementia, parkinsonism linked to chromosome 17 and Alzheimer's disease, tau proteins can self-assemble to paired helical filaments progressing to neurofibrillary tangles. In these diseases, collectively referred to as "tauopathies", alterations of diverse tau modifications including phosphorylation, metal ion binding, glycosylation, as well as structural changes of tau proteins have all been observed, indicating the complexity and variability of factors in the regulation of tau toxicity. Here, we review our current knowledge and hypotheses from relevant studies on tau toxicity, emphasizing the roles of phosphorylations, metal ions, folding and clearance control underlining tau etiology and their regulations. A summary of clinical efforts and associated findings of drug candidates under development is also presented. It is hoped that a more comprehensive understanding of tau regulation will provide us with a better blueprint of tau networking in neuronal cells and offer hints for the design of more efficient strategies to tackle tau-related diseases in the future.

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NAP (davunetide) modifies disease progression in a mouse model of severe neurodegeneration: Protection against impairments in axonal transport

Cited by 101 publications

References 108 publications

Tau-induced neurodegeneration: mechanisms and targets

Tau-induced neurodegeneration: mechanisms and targets

Microtubule-Tau Interaction as a Therapeutic Target for Alzheimer’s Disease

Behind the curtain of tauopathy: a show of multiple players orchestrating tau toxicity

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