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    • Naumann et al reported that the

    2018-11-09

    Naumann et al. (2010) reported that the absolute number of BrdU+ cells at 4 weeks after the last BrdU injection was similar between hAPP-I5 and control mice, which is inconsistent with our results. One possibility for this discrepancy might be the age of mice used in the studies. Six-week-old mice were used in Naumann\'s experiments whereas we used 10-week-old mice in our study. Neurogenesis was more active in younger mice, and therefore the effect of wild-type hAPP on neurogenesis might be counteracted partially by the active neurogenesis in younger mice. Wang et al. (2014) found that the dendritic growth of newborn neurons in the DG was significantly reduced in APP knockout mice, suggesting that both a too low and too high level of APP were detrimental to the development of newborn neurons. Driven by the same promoter, PDGF β-chain, hAPP-I5 mice expressed wild-type hAPP and hAPP-J20 mice expressed hAPP with Swedish and Indiana mutations in neurons, respectively (Mucke et al., 2000). The expression level of hAPP mRNA was similar in the brains of hAPP-I5 and hAPP-J20 mice. However, a previous study (Mucke et al., 2000) reported that the levels of Aβ were much higher in the CX-5461 cost of hAPP-J20 compared with hAPP-I5 mice, which we confirm in the present study. We found that the impairment of adult hippocampal neurogenesis was more prominent in hAPP-I5 mice than that of hAPP-J20 mice, suggesting that Aβ was not the major factor accounting for the impairment of adult neurogenesis. We also found that hAPP-J20 mice expressed more oligomeric Aβ in the hippocampus in comparison with hAPP-I5 mice, further suggesting that Aβ was not a main factor in the inhibition of adult neurogenesis. In a niche presented with a high level of Aβ, the proliferation, determination, and survival of hippocampal adult-born neurons were not affected (Yetman and Jankowsky, 2013), also suggesting that Aβ was not the major culprit for the impairment of adult neurogenesis. Retroviral delivery of α-CTF into neural progenitors affected the development of newborn neurons (Morgenstern et al., 2013), further suggesting that Aβ production was not necessary to inhibit adult hippocampal neurogenesis. Our results showed that downregulating Aβ levels by crossing hAPP-J20 mice with CST3 mice did not result in changes in adult hippocampal neurogenesis, providing more direct and convincing evidence that Aβ was not responsible for impaired adult hippocampal neurogenesis in both hAPP-I5 and hAPP-J20 mice used in our study. Because hAPP gene expression was driven by the PDGF β-chain promoter, hAPP could be derived from different types of neurons in both hAPP-I5 and hAPP-J20 mice. Therefore, it was unclear as to which sources of hAPP were to blame for the impaired adult neurogenesis. Recent studies showed that overexpression of hAPP exclusively in mature projection neurons in the forebrain did not affect neurogenesis in the adult hippocampus (Yetman and Jankowsky, 2013), whereas overexpression of hAPP in neural progenitor cells via retroviral delivery significantly affected the morphology and function of adult-born new neurons in the DG (Morgenstern et al., 2013), suggesting a cell-autonomous effect of APP on adult neurogenesis. However, we could not exclude the possibility that other sources of APP from either GABAergic neurons or even glial cells would affect adult neurogenesis. In fact, selective deletion of APP in GABAergic interneurons affected different processes of adult hippocampal neurogenesis (Wang et al., 2014). Further studies are warranted to dissect the definitive factor(s) affecting adult neurogenesis in hAPP-overexpressing mice.
    Experimental Procedures
    Author Contributions
    Acknowledgments We thank Fred Gage for the CAG-EGFP retroviral vector, Muming Poo for the POMC-GFP mice, Anders Grubb for the CST3 mice, Edward Koo for CT15 antibody, and Janssen Research & Development for antibodies 266, 21F12, and 3D6. Yanjiang Wang provided anti-APP antibody. This work was supported by grants from the Major State Basic Research Program of China (2014CB964602 to B.S.), the National Natural Science Foundation of China (91132713 to B.S.), the Zhejiang Provincial Natural Science Foundation of China (LR13H090001 to B.S.), and the Research Fund for the Doctoral Program of Higher Education of China (20110101120094 to B.S.).