Mechanistic Insight of Bivalent Compound 21MO as Potential Neuroprotectant for Alzheimer's Disease.

John Saathoff,Qun Chen,Kai Liu,Shijun Zhang,Jeremy Chojnacki,Edward Lesnefsky,Liu He

doi:10.3390/molecules21040412

John Saathoff, Qun Chen + Show 5 more

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https://doi.org/10.3390/molecules21040412

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Abstract

We have recently developed a bivalent strategy to provide novel compounds that potentially target multiple risk factors involved in the development of Alzheimer’s disease (AD). Our previous studies employing a bivalent compound with a shorter spacer (17MN) implicated that this compound can localize into mitochondria and endoplasmic reticulum (ER), thus interfering with the change of mitochondria membrane potential (MMP) and Ca2+ levels in MC65 cells upon removal of tetracycline (TC). In this report, we examined the effects by a bivalent compound with a longer spacer (21MO) in MC65 cells. Our results demonstrated that 21MO suppressed the change of MMP, possibly via interaction with the mitochondrial complex I in MC65 cells. Interestingly, 21MO did not show any effects on the Ca2+ level upon TC removal in MC65 cells. Our previous studies suggested that the mobilization of Ca2+ in MC65 cells, upon withdraw of TC, originated from ER, so the results implicated that 21MO may preferentially interact with mitochondria in MC65 cells under the current experimental conditions. Collectively, the results suggest that bivalent compounds with varied spacer length and cell membrane anchor moiety may exhibit neuroprotective activities via different mechanisms of action.

Highlights

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and the most common cause of dementia [1]
Theresults results demonstrated that 21MO can efficiently rescue MC65 cells from TC-removal induced necroptosis demonstrated that 21MO can efficiently rescue MC65 cells from TC-removal induced necroptosis (Figure 2A) and but could not rescue TNF/zVAD induced necroptosis in U937 cells (Figure 2B), (Figure 2A) and but could not rescue TNF/zVAD induced necroptosis in U937 cells (Figure 2B), suggesting that 17MN and 21MO may function in MC65 cells under the current experimental suggesting that 17MN and 21MO may function in MC65 cells under the current experimental conditions
Our previous studies demonstrated that 21MO exhibits inhibitory effects on the aggregation of small Aβ oligomersAβ (AβOs), but studies demonstrated that 21MO exhibits inhibitory effects on the aggregation of small AβOs, but with with a much weaker potency compared to its inhibition of MC65 cell death [12], suggesting that a much weaker potency compared to its inhibition of MC65 cell death [12], suggesting that the the inhibition of Aβ aggregation might only contribute partially towards its overall neuroprotective

Summary

Introduction

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and the most common cause of dementia [1] The complexity of this disease makes drug development efforts to provide effective disease modifying agents a challenging and unmet task since multiple pathogenic factors have been implicated in the development of AD, such as amyloid-β (Aβ) aggregates [2,3,4,5], oxidative stress, neuroinflammation, and mitochondria dysfunction, among others [6,7,8]. Further mechanistic studies employing one of Molecules 2016, 21, 412; doi:10.3390/molecules21040412 www.mdpi.com/journal/molecules

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