Probing different types of Alzheimer's - C&EN Global Enterprise (ACS

A hallmark of Alzheimer's disease is the accumulation of amyloid-β fibrils in the brain. It's still an open question whether structural differences i...
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Phosphorus garners an organic starring role that by using Na(OCP) in conjunction with an organoborane they could generate a boryl-substituted phosphaalkyne. Trimerization of this molecule yielded the needed Over time, chemists have synthesized an phosphorus analog, the triphosphabenzene C3P3 ring on a multigram scale. Subsequent incredible array of molecules that combine 2,4,6-tri(hydroxy)-1,3,5-triphosphinine, treatment of this borylated intermediate carbon, hydrogen, nitrogen, and oxygen. C3P3(OH)3, could play a similar role to with tert-butyl alcohol led to the target Second row periodic table elements such make phosphorus-containing plastics and C3P3(OH)3. as phosphorus and sulfur have made imcould serve as a valuable ligand for metal “Grützmacher and coworkers have made portant guest appearances a significant breakthrough,” OH OBR2 in compounds, but they tend says Jose M. Goicoechea of R2BCl not to form heavy analogs of the University of Oxford, (CH ) P P P P 3 3COH + common CHNO organic mol- 3 whose group first syntheHO P OH sized a phosphorus analog R2BO P OBR2 ecules. A research team based Na(OCP) at ETH Zurich has reported a of urea, H2PC(O)NH2, in Cyanuric acid R = isopinocampheyl rare exception by preparing 2013. “Their notable finding analog the phosphorus analog of promises to give rise to a lot cyanuric acid. catalysts (Angew. Chem. Int. Ed. 2016, DOI: of fascinating follow-up chemistry.” A six-membered heterocyclic ring, cy10.1002/anie.201610156). Grützmacher says there is no immediate anuric acid, C3N3(OH)3, and its derivatives The researchers thought they might plan to commercially develop the phosphoare often used as polymer cross-linking be able to make the phosphorus analog of rus analog. For now, his group is focusing agents and to make industrial chemicals cyanuric acid by first generating an analog on using the aromatic C3P3(OH)3 and its such as herbicides and dyes. Riccardo Suter, of isocyanic acid (HNCO) and trimerizing borylated and silylated derivatives as π–acZoltan Benkő, and Hansjörg Grützmacher, it. But their efforts to make HPCO failed. cepting ligands to prepare transition-metal who led the discovery team, believe the After some trial-and-error, they figured out complexes. —STEVE RITTER

Chemists prepare the phosphorus analog of cyanuric acid for the first time

STRUCTURAL BIOLOGY

Probing different types of Alzheimer’s structure seems to account for about 80% of the fibrils we derive from brain tissue,” Tycko says. Samples from one subtype, marked by rapid disease progression, show A hallmark of Alzheimer’s disease is the acThe NMR spectra revealed that for all signs of greater structural heterogeneity cumulation of amyloid-β fibrils in the brain. subtypes there’s one predominant fibril than the others. That heterogeneity may It’s still an open question whether structur- structure for the Aβ-40 peptide and two be a contributing factor in that form of al differences in these fibrils correlate with for the Aβ-42 peptide. For the Aβ-40 Alzheimer’s. different subtypes of the disease. peptide “in most cases the predominant “It is incredibly difficult to get structural To help answer that question, information about amyloid fibers, Robert Tycko and coworkers at even for simple in vitro proteins,” the National Institutes of Health says Martin T. Zanni, a chemistry have used brain tissue from paprofessor at the University of tients with one of three forms of Wisconsin, Madison, who studies Alzheimer’s disease to seed the amyloid formation. “It looks like formation of fibrils in the lab. Tycko has discovered the most These fibrils were made from important (or at least more pre40-residue and 42-residue amydominant) polymorph—the one loid-β peptides, common to the we should all be studying.” disease. Nuclear magnetic reso“We don’t know what the 3-D nance spectroscopy signatures structures look like and how difof the fibrils suggest that there ferent they are from structures may indeed be a correlation beThese 2-D 15N-13C NMR spectra show differences between that have been determined,” tween fibril structure and disease Aβ-40 fibrils seeded from patients with typical slowTycko says. “We’re now trying to manifestation (Nature 2017, DOI: progression Alzheimer’s disease (left) and rapid-progression figure out what those structures 10.1038/nature20814). Alzheimer’s (right). really are.”—CELIA ARNAUD

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C&EN | CEN.ACS.ORG | JANUARY 9, 2017

CREDIT: NAT U RE

Differences in fibril structure may correlate with different forms of the disease