Abstract
Considerable studies indicate huperzine A is a promising natural product to suppress neuronal damages induced by β-amyloid (Aβ), a key pathogenic event in the Alzheimer’s disease (AD). As an extension, the present study for the first time explored whether the beneficial profiles of huperzine A against oligomeric Aβ42 induced neurotoxicity are associated with the accumulation and detrimental function of intraneuronal/mitochondrial Aβ, on the basis of the emerging evidence that intracellular Aβ is more relevant to AD progression as compared with extracellular Aβ. Huperzine A treatment was shown to significantly attenuate the neurotoxicity of oligomeric Aβ42, as demonstrated by increased neuronal viability. Interestingly, our results proved that exogenous Aβ42 could accumulate intraneuronally in a dose- and time-dependent manner, while huperzine A treatment markedly reduced the level of intracellular Aβ42. Moreover, huperzine A treatment rescued mitochondrial dysfunction induced by oligomeric Aβ42, including adenosine triphosphate (ATP) reduction, reactive oxygen species (ROS) overproduction and membrane potential depolarization. Further study demonstrated that huperzine A also significantly reduced the level of Aβ42 in the mitochondria-enriched subcellular fractions, as well as the Aβ42 fluorescent signals colocalized with mitochondrial marker. This study indicates that interfering intracellular Aβ especially mitochondrial Aβ accumulation, together with ameliorating Aβ-associated mitochondrial dysfunction, may contribute to the protective effects of huperzine A against Aβ neurotoxicity. Above results may shed more light on the pharmacological mechanisms of huperzine A and provide important clues for discovering novel therapeutic strategies for AD.
Highlights
Alzheimer’s disease (AD), the most common cause of dementia, is a chronic disorder characterized by progressive decline in cognitive function [1]
More and more attentions have been attracted on addressing the contribution of intracellular Aβ in Aβ oligomers-induced neurotoxicity [7, 39], yielding vigorously growing researches on discovering associated novel therapeutic strategies for AD based on “Aβ cascade hypothesis”, during which employing small active molecules with potent pharmacological efficacy as probe is usually considered as an effective way [40]
As an extension of previous studies, we demonstrate for the first time that huperzine A, a natural product, possesses potent alleviative effect on oligomeric Aβ42-induced neuronal damage, which is closely associated with the reduced level of intracellular Aβ especially mitochondrial Aβ, as well as the ameliorated mitochondrial function
Summary
AD, the most common cause of dementia, is a chronic disorder characterized by progressive decline in cognitive function [1]. Compelling evidence shows that excessive accumulation of Aβ peptide in the brain is a central and perhaps defining event in the pathogenesis of AD [2, 3], “Aβ cascade hypothesis” is strongly supported by evidence of Aβ-related pathology and has been the focal point of research and pharmaceutical industry for the past twenty years [2, 4]. Afore-mentioned evidence has raised the prospect of discovering effective therapeutic strategies on blocking Aβ internalization from the extracellular space or its intracellular accumulation, especially under the circumstance that current pharmacological approaches against Aβ formation or immunization failed to gain promising efficacy on preventing and/or delaying AD progressing
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