Photooxygenation Catalysts That Sense Amyloid Structures of Amyloid-β: New Therapeutic Strategy for Alzheimer’s Disease by Catalysis

Neurotoxicity of aggregated amyloid-β (Aβ) peptide is considered to be the pathogenesis of Alzheimer’s disease. Although therapeutic approaches targeting Aβ have been intensively studied, the disease is currently incurable. Thus, a new approach should be developed to overcome the disease. A research group at The University of Tokyo developed a new photocatalyst that can sense and selectively oxygenate only amyloid structures of Aβ aggregates. The oxygenated Aβ aggregates exhibits remarkably low aggregation activity and neurotoxicity. Further improvement of the photocatalyst toward long-wavelength (low-energy) application will lead to a new therapeutic strategy for the treatment of Alzheimer’s disease.

Figure 1: Design and chemical structure of the photocatalyst developed by the group.

The group’s photocatalyst is composed of two faces (shown in red and blue) that are related by θ angle and active oxygens generate only when θ is fixed near zero. The group has successfully developed such a photocatalyst by additionally introducing bromo- (shown by red sphere) and carbon-atoms (shown by blue sphere) into Thioflavin skeleton (shown by gray sphere) that is known as an Aβ-binding compound.

Figure 2: Oxygenation mechanism by the photocatalyst.

The photocatalyst is excited by irradiation of visible light, and then it generates active oxygens to oxygenate Aβ aggregates only when the photocatalyst binds to amyloid structures (shown in red) of Aβ aggregates (θ angle of a photocatalyst is fixed near zero). On the other hand, the photocatalyst cannot oxygenate biologically active peptides or proteins that do not contain amyloid structures.

Figure 3: Oxygenation for Aβ and biologically active peptides.

The photocatalyst senses and selectively oxygenates only Aβ aggregates but not biologically active peptides, whereas the group’s previous photocatalyst oxygenates both of them. (AT4: Angiotensin-4, ME: Met-enkephalin, Ghr: Des-acyl ghrelin, Sst: Somatostatin)

Figure 4: Atomic force microscope (AFM) images of non-oxygenated (left) and oxygenated (right) Aβ.

Fibrillar Aβ aggregates are observed when Aβ is not oxygenated (left), while they are not observed when Aβ is oxygenated (right). Thus, oxygenated Aβ is not aggregative.

Figure 5: Attenuation of Aβ toxicity by photooxygenation.

Cell viability is decreased due to Aβ toxicity when the neuronal cells are treated with non-oxygenated Aβ (Compare A and B). On the other hand, cell viability recovered due to attenuated Aβ toxicity when Aβ is oxygenated by visible light irradiation in the presence of the photocatalyst (Compare B, C, and D).
* “Photocatalyst” indicated here is the group’s this time catalyst that additionally contains Aβ recognizing peptide.

Program Information

JST ERATO
Kanai Life Science Catalyst Project
Project Leader: Professor Motomu KANAI, The University of Tokyo

Journal Information

Atsuhiko Taniguchi, Yusuke Shimizu, Kounosuke Oisaki, Youhei Sohma, and Motomu Kanai. “Switchable photooxygenation catalysts that sense higher-order amyloid structures”. Nature Chemistry (2016), Published online 27 June 2016, doi: 10.1038/nchem.2550.

Contact

[About Research]
Motomu Kanai, Ph.D.
Professor, Graduate School of Pharmaceutical Sciences, The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, JAPAN
Tel: +81-3-5841-4830 Fax: +81-3-5684-5206
E-mail:

[About Program]
Takeshi Ohyama
Department of Research Project, JST
Tel: +81-3-3512-3528 Fax: +81-3-3222-2068
E-mail:

Japanese