sFRP3 inhibition improves age‐related cellular changes in BubR1 progeroid mice

Abstract

Wnt signaling is a well‐known molecular pathway in age‐related pathogenesis and therapy of disease. While prior studies have mainly focused on Wnt ligands or Wnt activators, the in vivo functions of naturally secreted Wnt inhibitors are not clear, especially in brain aging. Using BubR1H/H mice as a novel mouse model of accelerated aging, we report that genetic inhibition of sFRP3 restores the reduced body and brain size observed in BubR1H/H mice. Furthermore, sFRP3 inhibition ameliorates hypomyelination in the corpus callosum and rescues neural progenitor proliferation in the hippocampal dentate gyrus of BubR1H/H mice. Taken together, our study identifies sFRP3 as a new molecular factor that cooperates with BubR1 function to regulate brain development, myelination, and hippocampal neurogenesis.

Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

“…As a proof of concept that WβC‐signalling declines with increasing age, Bayod et al () reported decreased canonical Wnt‐signalling in the hippocampus of a senescence accelerated mouse‐prone 8 (SAMP8) mouse model of accelerated aging. More recently, Cho et al, () documented that inhibition of sFRP3 rescues neural progenitor proliferation in the hippocampal dentate gyrus of BubR1H/H mice (a novel mouse model of accelerated aging), and suggested that the endogenous Wnt inhibitor cooperates with BubR1 function to regulate brain development, myelination, and hippocampal neurogenesis. Finally, Kase et al () recently reported the involvement of WβC‐signalling in the p38‐induced age‐dependent decline of adult neurogenesis.…”

“…Unlike the effect of the Dkk family of Wnt‐antagonists on AD, the sFRP molecules have a more pleiotropic impact on the Wnt signalling cascade and may have an important involvement in neurodegeneration. Recently, the potential role of sFRPs on neurodegeneration, their likely involvement, and potential implications in treatment modalities of AD has been reviewed, and future studies will further define sFRPs as potential therapeutic modulators of WβC activation in a number of NDs including PD (Cho et al, ; L'Episcopo, Tirolo, Serapide, et al, ; Warrier et al, ).…”

“…Direct activation of canonical Wnt/Fzd/β-catenin cascade with: Fzd-LRP5/6 Wnts surrogates; SVZ-NSC-derived astrocyte's Wnt1, in blue; small Wnt activators targeting Axin-LRP6 (HLY78, SKL2001), PP2A agonists, in red (IQ1, Sodium selenite), directly interacting with multiple components of β-catenin destruction complex; GSK-3β antagonists, in red (VPA, LiCl, AR, BIO, CHIR, SB431542); or endogenous antagonists such as secreted FZD-related proteins, sFRPs (WAY310666), in red. bFGF, basic fibroblast growth factor; casein kinase 1α (CK1α); Dishevelled, Dvl; Fzd, frizzled; GSK-3β, glycogen synthase kinase 3β;NO-NSAID, nitric oxide-releasing non-steroidal anti-inflammatory drugs; Nrf2, nuclear factor erythroid 2-related factor 2; NSC, neural stem/progenitor cell; Nurr1, nuclear receptor related 1 protein; sFRP, secreted Frizzled-related proteins; SVZ, sub-ventricular zone; tumor suppressor adenomatous polyposis coli, APC; WβC-AC, Wnt/β-catenin signalling activation define sFRPs as potential therapeutic modulators of WβC activation in a number of NDs including PD (Cho et al, 2019;L'Episcopo, Tirolo, Serapide, et al, 2018b;Warrier et al, 2016).…”

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

“…A reduction in BubR1 protein in mice (BubR1 H/H mice) resulted in a systemic and neuronal progeria condition (Choi et al, ) and in impairment of adult hippocampal neurogenesis (Yang et al, ). The progeric conditions were partly ameliorated by targeted elimination/reduction of p16INK4‐positive cells (Baker et al, ), by enhancing Wnt signaling via loss of Dickkopf‐1 (Seib et al, ) or via inhibition of secreted frizzled‐related protein 3 (sFRP3) (Cho et al, ), both of which are endogenous Wnt antagonists. These findings suggest that (a) there is a role of genomic maintenance and aneuploidy in aging processes, and that (b) cell proliferation in the hippocampus is controlled by Wnt signaling.…”

Stem Cell Aging? Blame It on the Niche

“…Further, many studies have established altered Wnt signaling in the pathogenesis of aging. Elimination of the Wnt antagonist sfrp3 results in increased qNSC activation in the hippocampus (Sun et al, 2015), and genetic inhibition of sfrp3 rescues neural progenitor proliferation in the aged hippocampus (Cho et al, 2019). Adding to this series of studies, Kalamakis et al (2019) found that sfrp5, another Wnt antagonist in the sfrp family, was upregulated in aged qNSCs.…”