Intraperitoneal Administration of a Novel TAT-BDNF Peptide Ameliorates Cognitive Impairments via Modulating Multiple Pathways in Two Alzheimer's Rodent Models.

Lingqiang Zhu,Xinhua Liu,Xifei Yang,Ziyuan Guo,Deyi Liu,Xiaobin Luo,Qing Tian,Jian-Zhi Wang,Xiong Wang,Yuanyuan Wu

doi:10.1038/srep15032

Abstract

Although Alzheimer’s disease (AD) has been reported for more than 100 years, there is still a lack of effective cures for this devastating disorder. Among the various obstacles that hold back drug development, the blood-brain barrier (BBB) is one of them. Here, we constructed a novel fusion peptide by linking the active domain of brain-derived neurotrophic factor (BDNF) with an HIV-encoded transactivator of transcription (TAT) that has a strong membrane-penetrating property. After intraperitoneal injection, the eGFP-TAT could be robustly detected in different brain regions. By using scopolamine-induced rats and APPswe mice representing AD-like cholinergic deficits and amyloidosis, respectively, we found that intraperitoneal administration of the peptide significantly improved spatial memory with activation of the TrkB/ERK1/2/Akt pathway and restoration of several memory-associated proteins in both models. Administration of the peptide also modulated β-amyloid and tau pathologies in APPswe mice, and it increased the amount of M receptor with modulation of acetylcholinesterase in scopolamine-induced rats. We conclude that intraperitoneal administration of our TAT-BDNF peptide could efficiently target multiple molecular pathways in the brain and improve the cognitive functions in AD-like rodent models.

Highlights

Alzheimer’s disease (AD) has been reported for more than 100 years, there is still a lack of effective cures for this devastating disorder
The results showed that the levels of p-Akt and p-extracellular signal-regulated kinase 1/2 (Erk1/2) were significantly decreased in APPswe mice compared with APPwt mice and that administration of the TAT-brain-derived neurotrophic factor (BDNF) peptide restored the levels of p-Akt and p-Erk1/2 in APPswe mice (Fig. 2E,F)
While BDNF emerges as a promising target for AD therapeutics[21,22,23], the clinical application is largely hindered by its large molecular size, which prevents it from crossing the blood-brain barrier

Summary

Introduction

Alzheimer’s disease (AD) has been reported for more than 100 years, there is still a lack of effective cures for this devastating disorder. By using scopolamine-induced rats and APPswe mice representing AD-like cholinergic deficits and amyloidosis, respectively, we found that intraperitoneal administration of the peptide significantly improved spatial memory with activation of the TrkB/ERK1/2/Akt pathway and restoration of several memory-associated proteins in both models. We conclude that intraperitoneal administration of our TAT-BDNF peptide could efficiently target multiple molecular pathways in the brain and improve the cognitive functions in AD-like rodent models. The drugs approved by the United States Food and Drug Administration (FDA) for the clinical treatment of AD generally fall into two categories, i.e., acetylcholinesterase (AChE) inhibitors, such as tacrine, donepexil, and rivastigmine, and N-methyl-D-aspartate (NMDA) receptor antagonists, www.nature.com/scientificreports/. One major obstacle for the clinical application of BDNF is that this molecule cannot cross blood-brain barrier, mainly due to its large molecular weight

Methods

Results

Conclusion