Macyczko, Jesse R.

AbstractBackgroundThe accumulation of the amyloid‐β (Aβ) aggregates in the brain is a key pathological event in the development of Alzheimer’s disease (AD). The α‐secretase ADAM10 is responsible for cleavage of the amyloid precursor protein (APP) through a non‐amyloidogenic pathway, thereby preventing the generation of pathogenic Aβ in the brain. Secreted frizzled related protein‐1 (sFRP1), an endogenous antagonist of Wnt signaling, has recently been identified as a key negative modulator of ADAM10. Importantly, proteomic studies reveal that unregulated sFRP1 is one of the top Aβ‐correlated proteins in the human AD brains.MethodsWe determined the therapeutic potential of specific sFRP1 WAY316606 in the N2a/APP695swe cells and patient‐specific iPSC‐derived cerebral organoids.ResultsWe herein demonstrated that treatment of sFRP1 inhibitor WAY316606 resulted in augmentation of ADAM10 activity, upregulation of soluble APP‐α (sAPPα) production, and inhibition of Aβ generation in the N2a/APP695swe cells. Moreover, WAY316606 significantly enhanced ADAM10 activity, decreased Aβ production and inhibited tau phosphorylation in human AD patient‐specific iPSC‐derived cerebral organoids.ConclusionOur findings indicate that sFRP1 is a promising therapeutic target for AD.

The prevalence of Alzheimer’s disease is greater in women, but the underlying mechanisms remain to be elucidated. We herein demonstrated that α-secretase ADAM10 was downregulated and ADAM10 inhibitor sFRP1 was upregulated in 5xFAD mice. While there were no sex effects on ADAM10 protein and sFRP1 mRNA levels, female 5xFAD and age-matched non-transgenic mice exhibited higher levels of sFRP1 protein than corresponding male mice. Importantly, female 5xFAD mice accumulated more Aβ than males, and sFRP1 protein levels were positively associated with Aβ42 levels in 5xFAD mice. Our study suggests that sFRP1 is associated with amyloid pathology in a sex-dependent manner.

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of age‐related dementia characterized by the presence of amyloid‐β (Aβ) and tau pathologies leading to neurodegeneration and cognitive impairment. Wnt/β‐catenin signaling modulates multiple pathophysiological processes including synaptic plasticity, neuronal survival, neuroinflammation, Aβ production and tau phosphorylation, but this signaling pathway is greatly inhibited in the AD brain. Notably, two SNPs and an alternative splice variant of Wnt co‐receptor LRP6, which result in down‐regulation of Wnt/β‐catenin signaling, are associated with increased risk of developing AD. In addition, apoE4, the strongest risk factor of late‐onset AD, interacts with and decreases cell surface abundance of LRP6 in astrocytes. Studies from our laboratory have demonstrated that the level of LRP6 is significantly downregulated in human AD brains, and that deficiency in LRP6‐mediated Wnt/β‐catenin signaling leads to synaptic abnormalities and amyloid pathology in amyloid model mice. Therefore, LRP6 is an attractive therapeutic target for restoring Wnt/β‐catenin signaling in the AD brain.MethodIn our previous studies, we have discovered niclosamide, an FDA‐approved anthelminthic drug, inhibits Wnt/β‐catenin signaling via promoting LRP6 degradation. Herein, we demonstrated that CI‐994, an analog of niclosamide, exhibits opposite effects on LRP6 level and Wnt/β‐catenin signaling. Following structural optimization, we have generated a series of novel potent Wnt modulators.ResultThe leading compound W2A‐16 displays a good pharmacokinetic profile with high oral bioavailability and brain penetration. Importantly, W2A‐16 significantly activates Wnt/β‐catenin signaling and inhibits tau phosphorylation in AD patient‐specific iPSC‐derived cerebral organoids. Moreover, W2A‐16 attenuates amyloid pathology and gliosis and improves cognitive function in 5xFAD amyloid model mice. Further, W2A‐16 suppresses tau phosphorylation and neuroinflammation, attenuates body weight loss, and improves the survival of PS19 tauopathy mice.ConclusionTogether, these findings demonstrate that W2A‐16 is a strong drug candidate for AD therapy.