Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (9): 4447-4456.doi: 10.4103/NRR.NRR-D-25-00175

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Molecular pathways underlying amyloid precursor protein–mediated regulation of adult-born neurons

Haidong Hu1, 2, #, Huidong Li2, #, Yu Chen2, #, Jianwen Zhou2, Jian Chen2, Qihong Tang2, Xiaoshan Chen2, Jinxiang Jiang2, Mengyao Sun2, Dongjing Jia2, Wenyuan Xie2, Cheng Long2, *, Li Yang1, *#br#

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  1. 1School of Life Sciences, Guangzhou University, Guangzhou, Guangdong Province, China; 
    2School of Life Sciences, South China Normal University, Guangzhou, Guangdong Province, China
  • Online:2026-09-15 Published:2026-05-22
  • Contact: Li Yang, PhD, yang_li@gzhu.edu.cn; Cheng Long, PhD, longcheng@m.scnu.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 32170950 (to LY), 31970915 (to LY), 32371065 (to CL); the Natural Science Foundation of the Guangdong Province, No. 2023A1515010899 (to CL).

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Abstract: Cleavage of amyloid precursor protein (APP) produces toxic amyloid-beta peptides, which play a critical role in the pathogenesis of Alzheimer’s disease. Neuronal loss is a key feature of Alzheimer’s disease. Despite the importance of APP in the proliferation of neural progenitors and the survival of adult-born granule cells in the dentate gyrus, little is known about the effect of APP deficiency on neuronal electrophysiological activities and the survival of newly born neurons. Utilizing whole-cell patch-clamp recording in combination with retroviral labeling and immunofluorescent staining in Alzheimer’s disease model mice with App knockout (App–/–), we show that APP deficiency increased the number of adult-born granule cells at 4 weeks post-injection, but did not affect their intrinsic excitability or miniature current activity. In contrast, at 10 weeks post-injection, adult-born granule cells showed increased abundance and intrinsic excitability that were associated with abnormal dendritic morphology, increased miniature excitatory- and inhibitory-synaptic transmission, and decreased potassium-chloride-cotransporter 2 expression. Compared with adult-born granule cells at 10 week post-injection, mature granule cells exhibited decreased intrinsic excitability and potassium-chloride-cotransporter 2 expression alongside increased apoptosis in App–/– mice. Additionally, although App–/–mice showed abnormal freezing behavior and elevated mature granule cell activation during contextual fear conditioning, adult-born granule cells were not recruited in either App–/– or wild-type control mice. Taken together, these findings suggest that APP is required for adult-born granule cell maturation and that APP deficiency induces excitotoxicity in adult-born granule cells at 10 weeks post-injection, promoting subsequent apoptosis of mature granule cells. 

Key words: adult-born granule cellsl Alzheimer’s diseasel amyloid precursor proteinl apoptosisl fear conditioningl hippocampusl parvalbuminl potassium-chloride-cotransporter 2l whole-cell patch-clamp