Program

P.11 -- Poster, IWTCP-3

Date: Wednesday, 29 July 2015

Time: 08h30 - 10h00

Alzheimer’s Amyloid-$\beta$ Sequesters Caspase-3 via its C-terminal Tail

Nguyen Hoang Linh (1), Yu-Jen Chang (2), Hui-Ming Yu (2), Mai Suan Li (3*), and Yun-Ru Chen (2*)

(1) Institute for Computational Science and Technology, SBI Building, Quang Trung Software City, Tan Chanh Hiep Ward, District 12, Ho Chi Minh City, Vietnam (2) Genomics Research Center, Academia Sinica, Taiwan. 128, Academia Road, Sec. 2, Nankang Dist., Taipei 115, Taiwan. Tel. 886-2-2787-1275; Fax. 886-2-2789-8771; (3) Institute of Physics Polish Academy of Sciences, Al. Lotnikow 32/46, 02-668 Warsaw, Poland

Alzheimer’s disease (AD) is the most common neurodegenerative disease in the elderly. Amyloid- (A), the main consistent in the senile plaques found in the brain of AD patients, is considered the causative factor in AD pathogenesis. Clinical examination using AD brains have found that caspase-3 colocalizes with the senile plaques and biochemical studies have shown that Aβ is able to induce neuronal apoptosis via caspase-3 activation. Here, to investigate the possible direction effect of Aβ to caspase-3, we performed enzymatic studies and in silico study to understand the molecular mechanism of Aβ and caspase-3. We found Aβ conformers can directly sequester caspase-3 activity in which Aβ42 monomer is most potent with IC50 around 1.5 μM and has a better inhibition effect in comparison to Aβ40. The inhibition is non-competitive and the C-terminal region of Aβ plays an important role in the sequestration. The binding of Aβ to caspase-3 was studied by the docking and all-atom molecular dynamics simulations. It was shown that, in agreement with the experiments, Aβ42 has higher binding affinity than Aβ40 and the hydrophobic C-terminal plays a key role in the caspase-Aβ interaction. Overall, our result demonstrated that Aβ-induced caspase-3 activation in cells is from indirect events and Aβ is able to sequester caspase-3 activity via direct interaction.

Presenter: Nguyen Hoang Linh