Yale researchers reveal atomic structure of toxic Alzheimer's peptide
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Yale School of Medicine researchers have characterized the atomic structure of oligomeric amyloid beta, the toxic intermediate form of the peptide linked to Alzheimer's disease. The findings, published July 22 in Nature Communications, could guide development of more precise therapies that target the harmful oligomers without affecting healthy forms, even as two FDA-approved drugs that clear amyloid beta have shown limited benefits and severe side effects.
The Elusive Oligomer
For decades, scientists have known that amyloid beta forms plaques in Alzheimer's brains. However, increasing evidence points to oligomeric amyloid beta — an intermediate form between healthy peptides and plaques — as the primary driver of neuronal damage. Its structure remained unknown because it binds tightly to neuronal receptors, leaving little unbound peptide in the brain to study.
Structural Revelation
To overcome this, the Yale team treated Alzheimer's-affected brain tissue with a drug that displaced oligomeric amyloid beta from receptors, then purified it. The isolated peptides still damaged cultured human neurons, confirming biological activity. Using multiple microscopy methods, they visualized its atomic structure for the first time.
Drug Design Implications
The two FDA-approved amyloid-clearing drugs, aducanumab and lecanemab, offer limited cognitive benefits and can cause brain swelling or bleeding. The new structural data could enable therapies that specifically target the toxic oligomers while sparing functional forms, potentially reducing side effects. Over 6 million Americans live with Alzheimer's, a figure projected to double by 2060.
What's Next
The Yale team now plans to screen small molecules that could bind to the oligomeric structure. However, translating atomic insights into safe and effective drugs will require years of testing, and it remains uncertain whether targeting oligomers will prove more successful than current plaque-clearing strategies.
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Yale researchers reveal atomic structure of toxic Alzheimer's peptide
