NAP: Research and Development of a Peptide Derived from Activity-Dependent Neuroprotective Protein (ADNP)

Gozes, Illana; Morimoto, Bruce H.; Tiong, Jacqueline; Fox, Anthony W.; Sutherland, Karole; Dangoor, David; Holser‐Cochav, Miriam; Vered, Karin; Newton, Paul E.; Aisen, Paul S.; Matsuoka, Yasuji; Dyck, Christopher H. van; Thal, Leon J.

doi:10.1111/j.1527-3458.2005.tb00053.x

Cited by 132 publications

(133 citation statements)

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“…It should be noted that pharmacokinetic studies indicate that NAP enters the central nervous system through the blood, even with intranasal administration, i.e., NAP is found in the cerebrospinal fluid concurrently with being found in the plasma regardless of the administration route (e.g., Gozes et al, 2005;Morimoto et al, 2006). Measurements of NAP were conducted by a tandem liquid chromatography mass spectroscopy method.…”

Section: Discussionmentioning

confidence: 99%

“…Paclitaxel was shown to diminish the NAP-tubulin interaction in vitro (Divinski et al, 2006), suggesting that these two agents work, in part, through a related mechanism. Although paclitaxel is a nonselective tubulin-interacting agent and is associated with severe adverse effects in humans, NAP exhibits preferential interaction with neuronal tubulin (Divinski et al, 2006) as well as brain bioavailability (Gozes et al, 2000(Gozes et al, , 2005.…”

Section: Discussionmentioning

confidence: 99%

“…Peripheral administration of NAP has shown significant efficacy in various in vivo models and penetration into the brain at therapeutic levels (Gozes et al, 2005). Phase I clinical trials indicate that intranasally administered NAP is well tolerated and produces blood levels of the peptide expected, on the basis of animal studies, to reflect therapeutic concentrations in brain (Allon Therapeutics Inc., personal communication).…”

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confidence: 99%

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A Neuronal Microtubule-Interacting Agent, NAPVSIPQ, Reduces Tau Pathology and Enhances Cognitive Function in a Mouse Model of Alzheimer's Disease

Matsuoka

Jouroukhin

Gray

et al. 2008

J Pharmacol Exp Ther

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204

139

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Neurofibrillary tangles composed of aggregated, hyperphosphorylated tau in an abnormal conformation represent one of the major pathological hallmarks of Alzheimer's disease (AD) and other tauopathies. However, recent data suggest that the pathogenic processes leading to cognitive impairment occur before the formation of classic tangles. In the earliest stages of tauopathy, tau detaches from microtubules and accumulates in the cytosol of the somatodendritic compartment of cells. Either as a cause or an effect, tau becomes hyperphosphorylated and aggregates into paired helical filaments that comprise the tangles. To assess whether an agent that modulates microtubule function can inhibit the pathogenic process and prevent cognitive deficits in a transgenic mouse model with AD-relevant tau pathology, we administered the neuronal tubulin-preferring agent, NAPVSIPQ (NAP). Three months of treatment with NAP at an early-to-moderate stage of tauopathy reduced the levels of hyperphosphorylated soluble and insoluble tau. A 6-month course of treatment improved cognitive function. Although nonspecific tubulin-interacting agents commonly used for cancer therapy are associated with adverse effects due to their antimitotic activity, no adverse effects were found after 6 months of exposure to NAP. Our results suggest that neuronal microtubule interacting agents such as NAP may be useful therapeutic agents for the treatment or prevention of tauopathies.Neurofibrillary tangles containing hyperphosphorylated tau represent one of the principal pathological hallmarks of AD. Clinical progression of AD is tightly related to tau pathology (Braak and Braak, 1995), and a recent transgenic mouse study suggests that the pathogenic processes leading to cognitive impairment occur before the formation of classic tangles (Roberson et al

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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A Neuronal Microtubule-Interacting Agent, NAPVSIPQ, Reduces Tau Pathology and Enhances Cognitive Function in a Mouse Model of Alzheimer's Disease

Matsuoka

Jouroukhin

Gray

et al. 2008

J Pharmacol Exp Ther

Self Cite

204

139

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“…Significantly, this same peptide region appears to mediate the chaperone activity of αB-crystallin against a range of other disease-related, fibril-forming target proteins, including α-synuclein and β2-microglobulin [138,140]. At present, the development of therapeutics for Alzheimer's disease is largely focused on identifying inhibitors of fibril formation by Aβ peptides with some molecules that exhibit high inhibitory activity having progressed to stage III clinical trials [143][144][145]. The target protein specificity of these molecules (i.e.…”

Section: The Region(s) Of α-Crystallin Responsible For Target Proteinmentioning

confidence: 99%

Crystallin proteins and amyloid fibrils

Ecroyd

Carver

2008

Cell. Mol. Life Sci.

221

234

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Improper protein folding (misfolding) can lead to the formation of disordered (amorphous) or ordered (amyloid fibril) aggregates. The major lens protein, alpha-crystallin, is a member of the small heat-shock protein (sHsp) family of intracellular molecular chaperone proteins that prevent protein aggregation. Whilst the chaperone activity of sHsps against amorphously aggregating proteins has been well studied, its action against fibril-forming proteins has received less attention despite the presence of sHsps in deposits found in fibril-associated diseases (e.g. Alzheimer's and Parkinson's). In this review, the literature on the interaction of alpha B-crystallin and other sHsps with fibril-forming proteins is summarized. In particular, the ability of sHsps to prevent fibril formation, their mechanisms of action and the possible in vivo consequences of such associations are discussed. Finally, the fibril-forming propensity of the crystallin proteins and its implications for cataract formation are described along with the potential use of fibrillar crystallin proteins as bionanomaterials. Improper protein folding (misfolding) can lead to the formation of disordered (amorphous) or ordered (amyloid fibril) aggregates. The major lens protein, α-crystallin, is a member of the small heat-shock protein (sHsp) family of intracellular molecular chaperone proteins that prevent protein aggregation. Whilst the chaperone activity of sHsps against amorphously aggregating proteins has been well studied, its action against fibril-forming proteins has received less attention despite the presence of sHsps in deposits found in fibril-associated diseases (e.g. Alzheimer's and Parkinson's). In this review, the literature on the interaction of αB-crystallin and other sHsps with fibril-forming proteins is summarized. In particular, the ability of sHsps to prevent fibril formation, their mechanisms of action and the possible in vivo consequences of such associations are discussed. Finally, the fibril-forming propensity of the crystallin proteins and its implications for cataract formation are described along with the potential use of fibrillar crystallin proteins as bionanomaterials.

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“…Thus unlike linear peptides, NAP should form neither a typical α-helix nor the less common β-sheet structure, as a primary step in molecular self-assembly. Surprisingly, little is known about the initial steps of NAP assembly and what structures they embrace, although it has been shown to form random structures when studied with circular dichroism in various solvents [9]. Interest in the early steps of NAP self-assembly in aqueous media is largely due to its bioactivity at very low (sub-nanomolar) concentrations.…”

Section: Introductionmentioning

confidence: 99%