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N-cadherin-based adhesion enhances Abeta release and decreases Abeta42/40 ratio.

ABSTRACT: In neurons, Presenilin 1(PS1)/gamma-secretase is located at the synapses, bound to N-cadherin. We have previously reported that N-cadherin-mediated cell-cell contact promotes cell-surface expression of PS1/gamma-secretase. We postulated that N-cadherin-mediated trafficking of PS1 might impact synaptic PS1-amyloid precursor protein interactions and Abeta generation. In the present report, we evaluate the effect of N-cadherin-based contacts on Abeta production. We demonstrate that stable expression of N-cadherin in Chinese hamster ovary cells, expressing the Swedish mutant of human amyloid precursor protein leads to enhanced secretion of Abeta in the medium. Moreover, N-cadherin expression decreased Abeta(42/40) ratio. The effect of N-cadherin expression on Abeta production was accompanied by the enhanced accessibility of PS1/gamma-secretase to amyloid precursor protein as well as a conformational change of PS1, as demonstrated by the fluorescence lifetime imaging technique. These results indicate that N-cadherin-mediated synaptic adhesion may modulate Abeta secretion as well as the Abeta(42/40) ratio via PS1/N-cadherin interactions.

SUBMITTER: Uemura K

PROVIDER: S-EPMC2682435 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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N-cadherin-based adhesion enhances Abeta release and decreases Abeta42/40 ratio.

Uemura Kengo K Lill Christina M CM Banks Mary M Asada Megumi M Aoyagi Nobuhisa N Ando Koichi K Kubota Masakazu M Kihara Takeshi T Nishimoto Takaaki T Sugimoto Hachiro H Takahashi Ryosuke R Hyman Bradley T BT Shimohama Shun S Berezovska Oksana O Kinoshita Ayae A

Journal of neurochemistry 20081125 2

In neurons, Presenilin 1(PS1)/gamma-secretase is located at the synapses, bound to N-cadherin. We have previously reported that N-cadherin-mediated cell-cell contact promotes cell-surface expression of PS1/gamma-secretase. We postulated that N-cadherin-mediated trafficking of PS1 might impact synaptic PS1-amyloid precursor protein interactions and Abeta generation. In the present report, we evaluate the effect of N-cadherin-based contacts on Abeta production. We demonstrate that stable expressio ...[more]

PMID: 19046403

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Project description:Amyloid fibrils are highly ordered protein aggregates that are associated with several pathological processes, including prion propagation and Alzheimer's disease. A key issue in amyloid science is the need to understand the mechanical properties of amyloid fibrils and fibers to quantify biomechanical interactions with surrounding tissues, and to identify mechanobiological mechanisms associated with changes of material properties as amyloid fibrils grow from nanoscale to microscale structures. Here we report a series of computational studies in which atomistic simulation, elastic network modeling, and finite element simulation are utilized to elucidate the mechanical properties of Alzheimer's Abeta(1-40) amyloid fibrils as a function of the length of the protein filament for both twofold and threefold symmetric amyloid fibrils. We calculate the elastic constants associated with torsional, bending, and tensile deformation as a function of the size of the amyloid fibril, covering fibril lengths ranging from nanometers to micrometers. The resulting Young's moduli are found to be consistent with available experimental measurements obtained from long amyloid fibrils, and predicted to be in the range of 20-31 GPa. Our results show that Abeta(1-40) amyloid fibrils feature a remarkable structural stability and mechanical rigidity for fibrils longer than approximately 100 nm. However, local instabilities that emerge at the ends of short fibrils (on the order of tens of nanometers) reduce their stability and contribute to their disassociation under extreme mechanical or chemical conditions, suggesting that longer amyloid fibrils are more stable. Moreover, we find that amyloids with lengths shorter than the periodicity of their helical pitch, typically between 90 and 130 nm, feature significant size effects of their bending stiffness due the anisotropy in the fibril's cross section. At even smaller lengths (50 nm), shear effects dominate lateral deformation of amyloid fibrils, suggesting that simple Euler-Bernoulli beam models fail to describe the mechanics of amyloid fibrils appropriately. Our studies reveal the importance of size effects in elucidating the mechanical properties of amyloid fibrils. This issue is of great importance for comparing experimental and simulation results, and gaining a general understanding of the biological mechanisms underlying the growth of ectopic amyloid materials.

Dataset Information

N-cadherin-based adhesion enhances Abeta release and decreases Abeta42/40 ratio.

Publications

N-cadherin-based adhesion enhances Abeta release and decreases Abeta42/40 ratio.

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