Upregulation of Wnt2b produces neuroprotective effects by alleviating mitochondrial dysfunction in Alzheimer’s disease

Abstract

AbstractBackgroundAlzheimer disease (AD) is the most common neurodegenerative disorder leading to dementia in the elderly worldwide. Wnt signaling participates in multiple aspects of cellular function, and contributes to synapse formation, synaptic activity and neurogenesis in the brain, and dysfunction of Wnt signaling may aggravate the pathogenesis and progression of AD. Wnt2b has been studied in cancers or tumor‐related diseases, while the roles of Wnt2b in AD is still unknown. Wnt2b is also characterized as a mitochondria‐expressed protein which shuttles between mitochondria and the nucleus, and mitochondrial dysfunction contributes to the development and progression of the pathological process that underlies AD, especially at the early stage. This study investigated the relationship between plasma Wnt2b levels and AD, and explored the effect of Wnt2b on mitochondrial dysfunction in AD.MethodNormal cognitive (NC) and AD subjects, AD transgenic mice and in vitro model were used to investigated 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 sign aling. Mitochondrial structure was analyzed by electron microscopy. Flow cytometry was used to examine the intracellular calcium and neuronal apoptosis.ResultIn this study, we found plasma Wnt2b levels were lower in AD patients than NC subjects and positively correlated with cognitive performance (Figure 1). Similarly, Wnt2b was reduced in the hippocampus of AD mice and in vitro models (Figure 1). Next, Wnt2b overexpression and recombinant Wnt2b was used to endogenously (Figure 2) and exogenously (Figure 3) 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.ConclusionOur study highlights that Wnt2b decline is associated with cognitive impairment in AD, and Our findings may advance the understanding of the importance of Wnt family in AD, and we propose that Wnt2b might be a potential diagnostic indicator and therapeutic target for AD.