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Background: Alzheimer's disease (AD), is a progressive neurodegenerative disease that is characterized by cognitive loss. Most researchers believe that aggregation and accumulation of β-amyloid peptides (Aβ) in brain cells are the central pathological hallmark of this disease.Methods: Based on the amyloid hypothesis, a 10 amino acids β-sheet breaker peptide HPYD (His-Lys-Gln-Leu-Pro-Phe-Tyr-Glu-Glu-Asp) was designed according to the structure and sequence of the previous designed peptide H102. Accelerated stability test, thioflavine T (ThT) fluorescence spectral analysis and transmission electron microscopy (TEM) imaging were performed to detect the stability and inhibitory effects on the aggregation of Aβ1−42 by H102 and HPYD. FITC-labeled HPYD was first tested to determine whether it could be transferred along the olfactory pathway to the brain after nasal administration to mice. Subsequently, the Morris Water Maze (MWM) test for behavioral analysis was used to investigate the learning and memory ability of APP/PS1 transgenic mice by HPYD. Immunohistochemistry and western blot analysis was performed to determine the role of HPYD on Aβ and APP protein levels. In addition, microarray analysis was used to evaluate the effect of HPYD on gene expression in AD mouse models.Results: Our in vitro results demonstrated that HPYD had enhanced stability and inhibitory effects on Aβ1−42 aggregation compared to H102. HPYD could be delivered into the brain through nasal administration and improved the learning and memory ability in APP/PS1 transgenic mouse models by reducing Aβ and APP protein levels. In addition, microarray analyses suggested that several genes related to the inflammatory pathway, AD and gluco-lipid metabolism were dysregulated and could be restored to almost normal levels after HPYD administration to mice.Conclusions: Our results demonstrated that HPYD could be a potential therapeutic drug candidate for the treatment of AD.

Background: Alzheimer's disease (AD), is a progressive neurodegenerative disease that is characterized by cognitive loss. Most researchers believe that aggregation and accumulation of β-amyloid peptides (Aβ) in brain cells are the central pathological hallmark of this disease. Methods: Based on the amyloid hypothesis, a 10 amino acids β-sheet breaker peptide HPYD (His-Lys-Gln-Leu-Pro-Phe-Tyr-Glu-Glu-Asp) was designed according to the structure and sequence of the previous designed peptide H102. Accelerated stability test, thioflavine T (ThT) fluorescence spectral analysis and transmission electron microscopy (TEM) imaging were performed to detect the stability and inhibitory effects on the aggregation of Aβ1-42 by H102 and HPYD. FITC-labeled HPYD was first tested to determine whether it could be transferred along the olfactory pathway to the brain after nasal administration to mice. Subsequently, the Morris Water Maze (MWM) test for behavioral analysis was used to investigate the learning and memory ability of APP/PS1 transgenic mice by HPYD. Immunohistochemistry and western blot analysis was performed to determine the role of HPYD on Aβ and APP protein levels. In addition, microarray analysis was used to evaluate the effect of HPYD on gene expression in AD mouse models. Results: Our in vitro results demonstrated that HPYD had enhanced stability and inhibitory effects on Aβ1-42 aggregation compared to H102. HPYD could be delivered into the brain through nasal administration and improved the learning and memory ability in APP/PS1 transgenicmousemodels by reducing Aβ and APP protein levels. In addition, microarray analyses suggested that several genes related to the inflammatory pathway, AD and gluco-lipid metabolism were dysregulated and could be restored to almost normal levels after HPYD administration to mice. Conclusions: Our results demonstrated that HPYD could be a potential therapeutic drug candidate for the treatment of AD. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Alzheimer''s disease (AD) is characterized by vascular dysfunction, in addition to memory impairment. Previously we found that β-sheet breaker peptides (βSBPs) improved memory impairment induced by amyloid β-peptide Aβ40. In this study we investigated βSBP effects on vascular responses in a rat model of AD. Main methods: AD model was induced by bilateral injection of aged Aβ40 (3nmol) into the amygdala. βSBPs 15–22, 16–23 and 17–24 (30nmol) were injected into the amygdala 8days after Aβ40. The Aβ40 deposits were examined immunohistochemically in cerebral vessels and thoracic aorta. The effects on high-K+ contractility, phenylephrine (PE) contractility, acetylcholine (ACh) relaxation and sodium nitroprusside (SNP) relaxation were investigated in isolated thoracic aorta. Nitric oxide (NO) level in serum was investigated 14days after Aβ40. Key findings: Aβ40 was localized and it induced vascular damage in minute and small perforating cerebral vascular endothelium, and tunica intima (endothelial) and media (smooth muscle cells) of the thoracic aorta. In intact aorta, ACh-relaxation was decreased by Aβ40, an effect reduced by βSBPs 15–22 and 16–23. In denuded aorta, Aβ40 decreased PE-contractility. βSBP15–22 increased ACh-relaxation, whereas βSBP17–24 increased K+-contraction. Aβ40 decreased NO, an effect inhibited by the βSBP15–22. Significance: These results provide evidence that Aβ40-perverted endothelium-dependent relaxation and decreased serum NO in AD rats were improved differentially by the βSBP15–22. These results show the ability of Aβ40 to alter vascular responses. βSBPs appear to be promising candidate for prevention of these consequences and therapy of AD. [Copyright &y& Elsevier]

Current evidence supports the notion that β-amyloid deposits or Aβ intermediates may be responsible for the pathogenesis in Alzheimer's disease (AD) patients. In the present work, we have assessed the neuroprotective effect of the chronic intraperitoneal administration of a five-amino-acid β-sheet breaker peptide (iAβ5p) on the rat behavioral deficit induced by the intrahippocampal Aβ-fibrils injection. At 1 month after the injection, animals showed a partial reduction of the amyloid deposits formed and a decreased astrocytic response around the injection site. More importantly, we report that following the iAβ5p treatment, hippocampal-dependent spatial learning paradigms, including the standard Morris water maze and a working memory analysis, showed a significant prevention from impairments induced by Aβ deposits in the dorsal hippocampus. Thus, it is possible that a noninvasive treatment such as the one presented here with β-sheet breaker peptides may be used as a potential therapy for AD patients. [ABSTRACT FROM AUTHOR]

Aggregation of 42-residue amyloid β-protein (Aβ42) can be prevented by β-sheet breaker peptides (BSBps) homologous to LVFFA residues, which are included in a β-sheet region of Aβ42 aggregates. To enhance the affinity of BSBps to the Aβ42 aggregates, we designed and synthesized β-strand-fixed peptides (BSFps) whose side chains were cross-linked by ring closing metathesis. Conformation analysis verified that the designed peptides could be fixed in β-strand conformation. Among the synthesized pentapeptides, 1 and 12 , whose side chains of 2nd and 4th residues were cross-linked, significantly inhibited the aggregation of Aβ42. This suggested that β-strand-fixation of BSBps could enhance their inhibitory activity against the Aβ42 aggregation. However, pentapeptides 1 and 12 had little effect on morphology of Aβ42 aggregates (fibrils) and neurotoxicity of Aβ42 against SH-SY5Y cells. [ABSTRACT FROM AUTHOR]

The β-sheet breaker (BSB) peptides interfere with amyloid fibril assembly and used as therapeutic agents in the treatment of Alzheimer's disease (AD). In this regard, a simple yet effective in silico screening methodology was applied in the present study to evaluate a potential 867 pentapeptide library based on known BSB peptide, LPFFD, for destabilizing Aβ 42 protofibrils. The molecular docking based virtual screening was used to filter out pentapeptides having binding affinities stronger than LPFFD. In the next step, binding free energies of the top 10 pentapeptides were evaluated using the MM-PBSA method. The residue-wise binding free energy analysis reveals that two pentapeptides, PVFFE, and PPFYE, bind to the surface of Aβ 42 protofibril and another pentapeptide, PPFFE, bind in the core region of Aβ 42 protofibril. By employing molecular dynamics simulation as a post filter for the top-hit peptides from MM-PBSA, the pentapeptides, PPFFE, PVFFE, and PPFYE, have been identified as potential BSB peptides for destabilizing Aβ 42 protofibril structure. The conformational microstate analysis, a significant decrease in the β-sheet content of Aβ 42 protofibril, a loss in the total number of hydrogen bonds in Aβ 42 protofibril, Asp23-Lys28 salt bridge destabilization and analysis of the free energy surfaces highlight Aβ 42 protofibril structure destabilization in presence of pentapeptides. Among three top-hit pentapeptides, PPFFE displayed the most potent Aβ 42 protofibril destabilization effect that shifted the energy minima toward lowest value of β-sheet content as well as lowest number of hydrogen bonds in Aβ 42 protofibril. The in silico screening workflow presented in the study highlight an alternative tool for designing novel peptides with enhanced BSB ability as potential therapeutic agents for AD., (© 2019 Wiley Periodicals, Inc.)