Polysaccharides from Basella alba Protect Post-Mitotic Neurons against Cell Cycle Re-Entry and Apoptosis Induced by the Amyloid-Beta Peptide by Blocking Sonic Hedgehog Expression.

ABSTRACT

The amyloid-beta peptide (Aß) is the neurotoxic component in senile plaques of Alzheimer's disease (AD) brains. Previously we have reported that Aß toxicity is mediated by the induction of sonic hedgehog (SHH) to trigger cell cycle re-entry (CCR) and apoptosis in post-mitotic neurons. Basella alba is a vegetable whose polysaccharides carry immunomodulatory and anti-cancer actions, but their protective effects against neurodegeneration have never been reported. Herein, we tested whether polysaccharides derived from Basella alba (PPV-6) may inhibit Aß toxicity and explored its underlying mechanisms. In differentiated rat cortical neurons, Aß25-35 reduced cell viability, damaged neuronal structure, and compromised mitochondrial bioenergetic functions, all of which were recovered by PPV-6. Immunocytochemistry and western blotting revealed that Aß25-35-mediated induction of cell cycle markers including cyclin D1, proliferating cell nuclear antigen (PCNA), and histone H3 phosphorylated at Ser-10 (p-Histone H3) in differentiated neurons was all suppressed by PPV-6, along with mitigation of caspase-3 cleavage. Further studies revealed that PPV-6 inhibited Aß25-35 induction of SHH; indeed, PPV-6 was capable of suppressing neuronal CCR and apoptosis triggered by the exogenous N-terminal fragment of sonic hedgehog (SHH-N). Our findings demonstrated that, in the fully differentiated neurons, PPV-6 exerts protective actions against Aß neurotoxicity via the downregulation of SHH to suppress neuronal CCR and apoptosis.