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

Jia Xu,Kai Wang,Liping Wang,Ye Yuan,Shuwen Guan,Ruining Zhang,Hui Li

doi:10.3390/ijms19113304

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.

Highlights

Alzheimer’s disease (AD) is an age-related progressive neurodegenerative disorder mainly affecting people over 65 years of age
The DhHP-6-induced reduction in the diameter of Aβ1-42 was evaluated by dynamic light scattering (DLS)
Transmission Electron Microscopy (TEM) showed an alteration in the supramolecular structure of Aβ1-42 into uniformly dispersed spherical particles (Aβ1-42:DhHP-6 = 10 μM:10 μM molar ratio) after three days of DhHP-6 incubation at 37 ◦C (Figure 1D)

Summary

Introduction

Alzheimer’s disease (AD) is an age-related progressive neurodegenerative disorder mainly affecting people over 65 years of age. Several hypotheses have been proposed for the mechanistic basis of AD pathogenesis, and the amyloid cascade hypothesis is the most widely accepted [5] According to this hypothesis, β-amyloid peptides (Aβ1-40 and Aβ1-42) are produced due to aberrant β and γ-secretase proteolytic cleavage of the amyloid precursor protein (APP), which results in the extraneuronal accumulation of Aβ [6,7]. Persistent oxidative stress further aggravates Aβ production and aggregation and tau phosphorylation, leading to neuronal apoptosis, neuroinflammation, and metabolic disturbances [10,11] This vicious cycle of Aβ deposition and oxidative stress is the main driver of AD progression [12]. Targeting Aβ is a promising therapeutic strategy for AD, and can be achieved in the following was: (1) reducing Aβ peptide formation by enhancing the activity of α-secretase (non-amyloidogenic pathway), and reducing that of β and γ-secretase (amyloidogenic pathway) [9], (2) inhibiting the aggregation and formation of low molecular weight Aβ1-42 oligomers, which are more neurotoxic than other forms [13], and (3) enhancing Aβ clearance to restore oxidative stress homeostasis and control inflammation [14,15]

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