The Neuroprotective Peptide NAP Does Not Directly Affect Polymerization or Dynamics of Reconstituted Neural Microtubules

Abstract

NAP (Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln) is a neuroprotective peptide that shows cognitive protection in patients with amnestic mild cognitive impairment, a precursor to Alzheimer's disease. NAP exhibits potent neuroprotective properties in several in vivo and cellular models of neural injury. While it has been found in many studies to affect microtubule assembly and/or stability in neuronal and glial cells at fM concentrations, it has remained unclear whether it acts directly or indirectly on tubulin or microtubules. We analyzed the effects of NAP (1 fM-1 μM) on the assembly of reconstituted bovine brain microtubules in vitro and found that it did not significantly (p < 0.05) alter polymerization of either purified tubulin or of a mixture of tubulin and unfractionated microtubuleassociated proteins. NAP also had no significant effect (p < 0.05) on the growing and shortening dynamics of steady-state microtubules at their plus ends, nor did it alter the polymerization or dynamics of microtubules assembled in the presence of 3-repeat or 4-repeat tau. Thus, the neuroprotective activity of NAP does not appear to involve a direct action on the polymerization or dynamics of purified tubulin or microtubules.

Activity-dependent neuroprotector homeobox protein: A candidate protein identified in serum as diagnostic biomarker for Alzheimer's disease

“…NAP is a multi-functional peptide that protects neural cells. In previous studies, it was indicated that the NAP could prevent the ethanolinduced developmental toxicity, embryotoxicity, and has potential importance of ethanol effects on the pathophysiology of fetal alcohol syndrome (FAS) [47,48]. In AD research, the Apo E has been implicated as a risk factor.…”

“…In AD research, the Apo E has been implicated as a risk factor. The NAP is the neuroprotective peptide of Apo E deficiency and is able to break the amyloid plaque formation or degrade the β-amyloid toxicity [48,49]. Neurofibrillary tangles composed of aggregation, which are formed by hyperphosphorylated tau protein, are one of the major pathological hallmarks of AD.…”

Therapeutic strategies for tau mediated neurodegeneration

“…Intranasal administration of davunetide is undergoing phase II clinical trials for the treatment of tauopathies, including PSP, frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), CBD and progressive non-fluent aphasia (http://www.clinicaltrials.gov/ct2/show/NCT01056965). The main pharmacological action of davunetide is thought to be stabilisation of MTs in neurons,43 although the drug has other pleiotrophic effects and does not directly affect the polymerisation or dynamics of reconstituted neural MTs 44…”

Hyperdynamic Microtubules, Cognitive Deficits, and Pathology Are Improved in Tau Transgenic Mice with Low Doses of the Microtubule-Stabilizing Agent BMS-241027

“…In spinal cord injury and optic nerve crush models, local administration of paclitaxel improves axonal regeneration and motor function (Hellal et al, 2011;Sengottuvel et al, 2011). In addition, NAP, a peptide with possible indirect MT-stabilizing activity (Yenjerla et al, 2010), has pathological and behavioral benefits in several tauopathy models (Gozes et al, 2009). NAP is in Phase II clinical trials for tauopathy.…”