It has been known for a while that

It has been known for a while that oxygenation (the addition of oxygen) of Aβ can inhibit the formation of amyloids and diminish their cytotoxicity. Photo-oxygenation of Aβ started with fullerenes almost a decade ago by Toshima and co-workers. Later, porphyrins and polyoxometalates were used as well. Porphyrins were able to relieve Aβ toxicity in vivo in a Drosophila model of AD. Kanai and co-workers recently refined the photo-oxygenation approach by using a very elegant strategy, a kind of a “conformational prodrug,” to increase the specificity of amyloid degradation via photo-oxygenation. When the molecule is not bound to its target, a single bond rotates freely, and almost no 1O2 is produced upon irradiation (Figure 1A). Upon interaction with amyloids, the conformation of the compound is restricted, and as such, it is able to produce 1O2 upon irradiation (Figure 1B). In other words, the molecule acts as a photosensitizer only when it binds to its target (when it is switched on), restricting the ROS generation at only the target site. Together with the non-accumulation and short diffusion of 1O2, this system becomes very selective for amyloids (Figure 1C), in addition to being simple, elegant, and efficient. In this issue of Chem, Ni et al. present a significant improvement of this concept. First, they performed a rational design in several steps to shift the excitation wavelength of the photosensitizer to the near infrared (NIR) range and to increase the efficiency of 1O2 production. These are very important factors given that NIR allows deeper tissue penetration and less tissue damage than higher-energy light. The best compound in terms of photocatalytic efficiency and low cytotoxicity was compound 9 (Figure 1). Second, the authors performed in vitro, in cellulo, and in vivo experiments to evaluate the efficacy and specificity of 9. Compound 9 was able to oxygenate Aβ histone methyltransferase under NIR irradiation (780 nm) in buffer, in AD mice brain lysates, and in cell culture. Photo-oxygenation was more efficient toward aggregated Aβ than toward soluble Aβ and other tested non-amyloid peptides. Importantly, the studies in cell culture showed that NIR irradiation in the presence of 9 decreased the cell toxicity of Aβ, indicating that oxygenation of Aβ suppresses the toxic Aβ aggregates. In vivo experiments showed that administration of compound 9 to the hippocampus of an AD model mouse and NIR irradiation (30 min/day over a week) yielded a significant decrease in Aβ1-42 concentration (ca. 50% lower than that of the control). Therefore, compound 9 can efficiently and selectively oxygenate Aβ aggregates via irradiation of NIR light in vitro to in vivo, and such oxygenated Aβ is less toxic to cells in culture. Moreover, compound 9 seems to have no significant inherent cytotoxicity, even under NIR irradiation. This work is an inspired and significant step toward a more specific and efficient degradation of Aβ and is thus of strong interest in terms of AD therapy. Importantly, compound 9 is likely to also recognize other types of amyloids, including peripheral ones, where irradiation is more straightforward and no BBB penetration is needed (a property not yet shown for 9). Prion fibrils could also be a target, given that prions often turn on classical amyloid dyes such as thioflavin T (ThT). What are the next steps, and what could be the limitations to overcome?
Introduction Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder, accounting for 60%–80% of the more than 40 million cases of dementia worldwide.1, 2, 3 One pathological hallmark of AD is the accumulation of amyloid-β (Aβ) peptide as extracellular plaques in the brain.4, 5, 6 Aβ is a 38- to 42-amino acid peptide that is produced by proteolysis of amyloid precursor protein, APP. Some forms of Aβ are prone to aggregation and plaque formation, which is thought to initiate a cascade of pathological events associated with the development and progression of AD. Thus, targeting Aβ has been a major focus of therapeutic development for AD.1, 3, 7