Journal
MOLECULAR NEUROBIOLOGY
Volume 56, Issue 1, Pages 465-489Publisher
SPRINGER
DOI: 10.1007/s12035-018-1098-5
Keywords
Alzheimer's disease (AD); Caspase-3; Cyclin D1; Histone H3; Proliferating cell nuclear antigen (PCNA); Retinoblastoma protein (pRb)
Categories
Funding
- Ministry of Science and Technology in Taiwan [MOST 103-2314-B-010-013MY3, MOST 104-2314-B-010-014-MY2, MOST 106-2314-B-010-018MY3, MOST 104-2314-B-037-029, MOST 105-2314-B-037-002]
- Kaohsiung Medical University and Hospital [KMUH 103-3T16, KMUH 104-4R53]
- Department of Health in Taipei City Government [10501-62-050, 10601-62-003]
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Amyloid beta-peptide (A), 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 As 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 A-induced Id1 and SHH contribute to cell cycle reentry leading to apoptosis in neurons. We found that A 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, A 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 A-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 A. Taken together, our results revealed the critical roles of Id1 and SHH mediating A-dependent cell cycle reentry and subsequently caspase-dependent apoptosis in the fully differentiated post-mitotic neurons, at least in vitro.
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