Upregulation of Wnt2b exerts neuroprotective effect by alleviating mitochondrial dysfunction in Alzheimer's disease.

AIMS: This study investigated the relationship between plasma Wnt2b levels and Alzheimer's disease (AD), and explored the effect of Wnt2b on mitochondrial dysfunction in AD. METHODS: Healthy and AD subjects, AD transgenic mice, and in vitro models were used to investigate the roles of Wnt2b in abnormalities in canonical Wnt signaling and mitochondria in AD. RT-qPCR, immunoblotting, and immunofluorescence analysis were performed to assay canonical Wnt signaling. Mitochondrial structure was analyzed by electron microscopy. Flow cytometry was used to examine the intracellular calcium and neuronal apoptosis. RESULTS: Plasma Wnt2b levels were lower in AD patients and positively correlated with cognitive performance. Similarly, Wnt2b was reduced in the hippocampus of AD mice and in vitro models. Next, Wnt2b overexpression and recombinant Wnt2b were used to endogenously and exogenously upregulate Wnt2b levels. Upregulation of Wnt2b could effectively prevent downregulation of canonical Wnt signaling, mitochondrial dysfunction in in vitro AD models. Subsequently, intracellular calcium overload and neuronal damage were ameliorated. CONCLUSIONS: Our study highlights that Wnt2b decline is associated with cognitive impairment in AD, and upregulation of Wnt2b can exert neuroprotective effects in AD, particularly in ameliorating mitochondrial dysfunction.

CaMKIIα Signaling Is Required for the Neuroprotective Effects of Dl-3-n-Butylphthalide in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of neurodegenerative disease and most anti-AD drugs have failed in clinical trials; hence, it is urgent to find potentially effective drugs against AD. DL-3-n-butylphthalide (NBP) is a compound extracted from celery seed and is a multiple-target drug. Several studies have demonstrated the neuroprotective effects of NBP on cognitive impairment, but the mechanisms of NBP remains relatively unexplored. In this study, we found that NBP could alleviated the increase of intracellular Ca2+ and reversed down-regulation of Ca2+/calmodulin-dependent protein kinase alpha (CaMKIIα) signaling and rescued neuronal apoptosis in SH-SY5Y cells treated by Aß oligomers. However, these neuroprotective effects of NBP on neuronal damage and CaMKIIα signaling were abolished when CaMKIIα expression was knocked down or its activity was inhibited. Thus, our findings suggested that CaMKIIα signaling was required for the neuroprotective effects of NBP in AD and provided an improved basis for elucidating the mechanism and treatment of NBP in AD.

Toxic amyloid-ß oligomers induced self-replication in astrocytes triggering neuronal injury.

BACKGROUND: Soluble amyloid-ß oligomer (AßO) induced deleterious cascades have recently been considered to be the initiating pathologic agents of Alzheimer's disease (AD). However, little is known about the neurotoxicity and production of different AßOs. Understanding the production and spread of toxic AßOs within the brain is important to improving understanding of AD pathogenesis and treatment. METHODS: Here, PS1V97L transgenic mice, a useful tool for studying the role of AßOs in AD, were used to identify the specific AßO assembly that contributes to neuronal injury and cognitive deficits. Then, we investigated the production and spread of toxic Aß assemblies in astrocyte and neuron cultures, and further tested the results following intracerebroventricular injection of AßOs in animal model. FINDINGS: The results showed that cognitive deficits were mainly caused by the accumulation of nonameric and dodecameric Aß assemblies in the brains. In addition, we found that the toxic AßOs were duplicated in a time-dependent manner when BACE1 and apolipoprotein E were overexpressed, which were responsible for producing redundant Aß and forming nonameric and dodecameric assemblies in astrocytes, but not in neurons. INTERPRETATION: Our results suggest that astrocytes may play a central role in the progression of AD by duplicating and spreading toxic AßOs, thus triggering neuronal injury. FUND: This study was supported by the Key Project of the National Natural Science Foundation of China; the National Key Scientific Instrument and Equipment Development Project; Beijing Scholars Program, and Beijing Brain Initiative from Beijing Municipal Science & Technology Commission.