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A Novel Peroxidase Mimics and Ameliorates Alzheimer’s Disease-Related Pathology and Cognitive Decline in Mice

1
School of Life Sciences, Jilin University, Changchun 130012, China
2
Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun 130012, China
3
Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, Jilin Universtiy, Changchun 130012, China
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(11), 3304; https://doi.org/10.3390/ijms19113304
Received: 22 September 2018 / Revised: 14 October 2018 / Accepted: 19 October 2018 / Published: 24 October 2018
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder in the elderly, which is characterized by the accumulation of amyloid β (Aβ) plaques, oxidative stress, and neuronal loss. Therefore, clearing Aβ aggregates and reducing oxidative stress could be an effective therapeutic strategy for AD. Deuterohemin-AlaHisThrValGluLys (DhHP-6), a novel deuterohemin-containing peptide mimetic of the natural microperoxidase-11 (MP-11), shows higher antioxidant activity and stability compared to the natural microperoxidases. DhHP-6 possesses the ability of extending lifespan and alleviating paralysis in the Aβ1-42 transgenic Caenorhabditis elegans CL4176 model of AD, as shown in our previous study. Therefore, this study was aimed at exploring the neuroprotective effect of DhHP-6 in the APPswe/PSEN1dE9 transgenic mouse model of AD. DhHP-6 reduced the diameter and fiber structure of Aβ1-42 aggregation in vitro, as shown by dynamic light scattering and transmission electron microscope. DhHP-6 exerted its neuroprotective effect by inhibiting Aβ aggregation and plaque formation, and by reducing Aβ1-42 oligomers-induced neurotoxicity on HT22 (mouse hippocampal neuronal) and SH-SY5Y (human neuroblastoma) cells. In the AD mouse model, DhHP-6 significantly ameliorated cognitive decline and improved spatial learning ability in behavioral tests including the Morris water maze, Y-maze, novel object recognition, open field, and nest-building test. Moreover, DhHP-6 reduced the deposition of Aβ plaques in the cerebral cortex and hippocampus. More importantly, DhHP-6 restored the morphology of astrocytes and microglia, and significantly reduced the levels of pro-inflammatory cytokines. Our findings provide a basis for considering the non-toxic, peroxidase mimetic DhHP-6 as a new candidate drug against AD. View Full-Text
Keywords: Alzheimer’s disease; deuterohemin-AlaHisThrValGluLys; cognitive ability; Aβ deposition; oxidative stress; pro-inflammatory cytokines Alzheimer’s disease; deuterohemin-AlaHisThrValGluLys; cognitive ability; Aβ deposition; oxidative stress; pro-inflammatory cytokines
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Xu, J.; Wang, K.; Yuan, Y.; Li, H.; Zhang, R.; Guan, S.; Wang, L. A Novel Peroxidase Mimics and Ameliorates Alzheimer’s Disease-Related Pathology and Cognitive Decline in Mice. Int. J. Mol. Sci. 2018, 19, 3304.

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