Alzheimer s disease AD is the

Alzheimer\'s disease (AD) is the most common neurodegenerative disorder. The pathological hallmarks of AD include extracellular amyloid plaques consisting mainly of Aβ42, and intracellular neurofibrillary tangles comprising mainly hyperphosphorylated tau (Serrano-Pozo et al., 2011). Previous studies reported that adult hippocampal neurogenesis was affected in AD patients. However, results from different groups were not consistent (Boekhoorn et al., 2006; Jin et al., 2004; Li et al., 2008). On the other hand, it was nearly impossible to investigate systematically the effects of AD on different stages of adult neurogenesis by using samples from AD patients. Therefore, animal models simulating key pathological features of AD provided invaluable tools to study the effects of different factors involved in AD on adult neurogenesis (Epis et al., 2010). Transgenic mice overexpressing human amyloid precursor proteins (hAPP) are common animal models of AD. Although data from different studies were still controversial, most experimental results indicated that adult hippocampal neurogenesis was adversely disturbed in mice with hAPP overexpression (Chuang, 2010; Donovan et al., 2006; Haughey et al., 2002). However, hAPP-overexpressing mice contained higher levels of both hAPP and amyloid β (Aβ) in the androgen receptor compared with nontransgenic controls (Mucke et al., 2000). It remained unknown, therefore, whether a high level of hAPP or Aβ was the major factor accounting for impaired adult neurogenesis in these models. Besides, mice overexpressing mutant hAPP were used in most of the studies. The effects of wild-type hAPP, which is harbored in most sporadic AD patients, on adult neurogenesis were far from clear. In the present study, we investigated adult hippocampal neurogenesis in hAPP-I5 mice that overexpressed wild-type hAPP in neurons driven by platelet-derived growth factor (PDGF) β-chain promoter. Furthermore, we compared adult neurogenesis in hAPP-I5 and hAPP-J20 mice. These two lines of mice expressed similar levels of hAPP mRNA but very different levels of Aβ in the brain (Mucke et al., 2000). We found that adult hippocampal neurogenesis was impaired in hAPP-I5 mice. More interestingly, the degree of impairment of neurogenesis was more prominent in hAPP-I5 mice compared with that of hAPP-J20 mice, and downregulating Aβ levels did not affect the number of newborn neurons in hAPP-J20 mice, suggesting that Aβ was not the major factor accounting for impaired adult hippocampal neurogenesis.
Results
Discussion Adult hippocampal neurogenesis has been investigated in different lines of mice overexpressing mutant hAPP (Chuang, 2010; Donovan et al., 2006; Yu et al., 2009). Surprisingly, however, studies on the effects of wild-type hAPP on adult neurogenesis have been very rare, considering that most AD patients did not express the mutant forms of APP (Soldner and Jaenisch, 2015). In an earlier study, BrdU-labeling results indicated that a high level of wild-type hAPP reduced the proliferative ability of progenitor cells and promoted the survival of newborn neurons in the DG (Naumann et al., 2010). In our present study, we used both BrdU labeling and retroviral vector expressing GFP to investigate the changes in numbers and morphological features of newborn neurons, respectively. Consistent with a previous report (Naumann et al., 2010), we found that the proliferative activity of progenitor cells in the DG of hAPP-I5 mice was decreased, as shown by BrdU labeling and MCM2 immunostaining. By crossing hAPP-I5 mice with Nestin-GFP mice (a reporter line of neural stem cells) (Mignone et al., 2004), we found that the depletion of the neural progenitor cell population was accelerated in the DG of hAPP-I5 mice (data not shown). Similarly, neural progenitor proliferation in the DG was increased in APP knockout mice (Wang et al., 2014). These data suggested that APP from both human and mouse inhibited the proliferative ability of neural progenitors in the DG. We found that the number of DCX+ immature neurons in the DG of hAPP-I5 mice was fewer than that in nontransgenic control mice. This result was confirmed by crossing hAPP-I5 with POMC-GFP mice, in which GFP could label immature neurons in the DG with similarly aged DCX+ neurons (Overstreet et al., 2004). Furthermore, we found not only that the number of mature newborn neurons (BrdU+/NeuN+) decreased, but also that the dendrites of newborn neurons in the DG of hAPP-I5 mice were shorter than those of control mice. These results indicated that different developmental stages of adult hippocampal neurogenesis were affected by high levels of wild-type hAPP.