Abstract
Alzheimer's disease (AD) is proposed to be induced by abnormal aggregation of amyloidβ in the brain. Here, we designed a brain-permeable peptide nanofiber drug from a fragment of heat shock protein to suppress aggregation of the pathogenic proteins. To facilitate delivery of the nanofiber into the brain, a protein transduction domain from Drosophila Antennapedia was incorporated into the peptide sequence. The resulting nanofiber efficiently suppressed the cytotoxicity of amyloid βby trapping amyloid β onto its hydrophobic nanofiber surface. Moreover, the intravenously or intranasally injected nanofiber was delivered into the mouse brain, and improved the cognitive function of an Alzheimer transgenic mouse model. These results demonstrate the potential therapeutic utility of nanofibers for the treatment of AD.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia [1] characterized by senile plaque (SP), which is the extracellular deposit of amyloidβ(Aβ)aggregates [2],and neurofibrillary tangle, which is the intracellular accumulation of phosphorylated tau protein [3]
At first,we examined nanofiber formation of a cationic variant of αAC(71–88) that was fused to a protein transduction domain from Drosophila Antennapedia i.e., αAC(71–88)Antp (FVIFLDVKHFSPEDLTVKRQIKIWFQNRRMKWKK)
The time trace of thioflavinT (ThT) fluorescence intensity showed that amyloid fibril formation of 100 μg/ml Aβ(1–42) was accelerated in the presence of 100 μg/ ml αAC(71–88)Antp nanofiber, whereas αAC(71–88)Antp nanofiber itself had little effect on the ThT fluorescence at this concentration. These results suggest that the major effect of the positively chargedαAC(71–88) Antp nanofiber is to accelerate the aggregation of anionic Aβ(1–42)
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia [1] characterized by senile plaque (SP), which is the extracellular deposit of amyloidβ(Aβ)aggregates [2],and neurofibrillary tangle, which is the intracellular accumulation of phosphorylated tau protein [3]. The therapeutic use of peptide inhibitors of pathological aggregation has been proposed for the treatment of AD [7, 8]. Synthetic peptides from α-crystallin have been extensively examined for inhibiting pathological aggregation, as fragments of this protein are unlikely to induce an immune response [9,10,11]. Α-Crystallin, a member of the small heat shock superfamily of proteins, can prevent protein aggregation [9, 12,13,14,15,16]. The α-crystallin protein consists of two closely related subunits, A and B (20 kDa each), and displays a β-sheet rich structure [17]. Synthetic peptides of α-crystallin corresponding to the substrate binding regions of the A and B subunits inhibit
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