Molecular Neurobiology

, Volume 56, Issue 1, pp 465–489 | Cite as

Id1 and Sonic Hedgehog Mediate Cell Cycle Reentry and Apoptosis Induced by Amyloid Beta-Peptide in Post-mitotic Cortical Neurons

  • A-Ching Chao
  • Chien-Hui Chen
  • Shih-Hsin Chang
  • Chao-Tzu Huang
  • Wei-Chao Hwang
  • Ding-I YangEmail author


Amyloid beta-peptide (Aβ), the neurotoxic component of senile plaques in Alzheimer’s disease (AD) brains, is known to trigger cell cycle reentry in post-mitotic neurons followed by apoptosis. However, the underlying mechanisms remain unclear. Recently, we have reported that Aβs stimulate the expression of inhibitor of differentiation-1 (Id1) to induce sonic hedgehog (SHH) (Hung et al., Mol Neurobiol 53(2):793–809, 2016), and both are mitogens capable of triggering cell cycle progression. In this work, we tested the hypothesis that Aβ-induced Id1 and SHH contribute to cell cycle reentry leading to apoptosis in neurons. We found that Aβ triggered cell cycle progression in the post-mitotic neurons, as indicated by the increased expression of two G1-phase markers including cyclin D1 and phosphorylated retinoblastoma protein (pRb), two G2-phase markers such as proliferating cell nuclear antigen (PCNA) and incorporation of 5-bromo-2′-deoxyuridine (BrdU) into newly synthesized DNA, as well as the mitotic marker histone H3 phosphorylated at Ser-10. As expected, Aβ also enhanced caspase-3 cleavage in the cortical neurons. Id1 siRNA, the neutralization antibody against SHH (SHH-Ab), and the cyclin-dependent kinase (CDK)-4/6 inhibitor PD0332991 all attenuated, in part or in full, the Aβ-induced expression of these cell cycle markers. Indeed, exogenous recombinant Id1 protein and the biologically active N-terminal fragment of SHH (SHH-N) were both sufficient to enhance the expression of cell cycle markers independent of Aβ. Taken together, our results revealed the critical roles of Id1 and SHH mediating Aβ-dependent cell cycle reentry and subsequently caspase-dependent apoptosis in the fully differentiated post-mitotic neurons, at least in vitro.


Alzheimer’s disease (AD) Caspase-3 Cyclin D1 Histone H3 Proliferating cell nuclear antigen (PCNA) Retinoblastoma protein (pRb) 


Funding Information

This study was supported by the Ministry of Science and Technology in Taiwan (MOST 103-2314-B-010-013MY3, MOST 104-2314-B-010-014-MY2, and MOST 106-2314-B-010-018MY3 to Ding-I Yang; MOST 104-2314-B-037-029 and MOST 105-2314-B-037-002 to A-Ching Chao), Kaohsiung Medical University and Hospital (KMUH 103-3T16 and KMUH 104-4R53 to A-Ching Chao), and Department of Health in Taipei City Government (10501-62-050 and 10601-62-003 to Ding-I Yang and Wei-Chao Hwang).


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Authors and Affiliations

  1. 1.Department of Neurology, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  2. 2.Department of NeurologyKaohsiung Medical University HospitalKaohsiungTaiwan
  3. 3.Institute of Brain Science and Brain Research CenterNational Yang-Ming UniversityTaipei CityTaiwan
  4. 4.Department of NeurologyTaipei City HospitalTaipeiTaiwan

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