Abstract
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that has no effective therapies. Prickle planar cell polarity protein 2 (Prickle2), is an important cytoplasmic regulator of Wnt/PCP signaling. It has been reported that Prickle2 deficiency reduced neurite outgrowth levels in mouse N2a cells and led to autism-like behaviors and hippocampal synaptic dysfunction in mice. However, much less is known about the relationship of Prickle2 to AD pathogenesis. RT-qPCR, Western blot and IHC results showed that the mRNA and protein levels of Prickle2 were reduced in APP/PS1/Tau transgenic (3xTg) mice. Intravenous injection of Prickle2-overexpressing AAV-PHP.eB vectors improved the cognitive deficits in 3xTg mice. We also demonstrated that Prickle2 could repress oxidative stress and neuroinflammation, ameliorate the amyloid β (Aβ) plaque pathology and reduce Tau hyperphosphorylation in APP/PS1 mice. Further investigation of the mechanism of Prickle2 in AD revealed that Prickle2 inhibited Wnt/PCP/JNK pathway in vivo and in vitro. Our results suggest that Prickle2 might be a potential candidate for the diagnosis and treatment of AD.
Highlights
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder with a high incidence rate among the elderly worldwide
These results indicated that the downregulation of Prickle2 in 3 × Tg-AD mouse model might be related to AD etiology
Many molecules have been proven to be involved in the pathogenesis of AD, the etiology of AD remains unclear
Summary
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder with a high incidence rate among the elderly worldwide. It is characterized by progressive memory loss, cognitive dysfunctions and dementia (Whitaker et al, 2014). Wnt/PCP signaling contains upstream canonical Wnt signaling pathway components, such as Wnt5A, Wnt5B, and Wnt, for the transduction of Wnt/PCP signals, followed by several transmembrane protein receptors of the PCP core components, Frizzled (FZD), Dishevelled (DSH), Vangl (van Gogh-like) and the cytoplasmic regulator Prickle (Katoh, 2005; Barrow, 2006; VanderVorst et al, 2019). Most recently, intriguing studies have implicated the involvement of Prickle in the pathogenesis of nervous system diseases. The exact function of Prickle in the etiology of AD is poorly understood, and whether Prickle regulates Aβ generation and cognitive functions in AD is of interest
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