cannabidiol and palbociclib

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.

Topics: Amyloid beta-Peptides; Animals; Apoptosis; Cannabidiol; Caspase 3; Cells, Cultured; Cerebral Cortex; Hedgehog Proteins; Humans; Inhibitor of Differentiation Protein 1; Mitosis; Models, Biological; Neurons; Neurotoxins; Peptide Fragments; Phosphorylation; Piperazines; Proliferating Cell Nuclear Antigen; Protein Kinase Inhibitors; Pyridines; Rats, Sprague-Dawley; RNA, Small Interfering; S Phase