24 Apr 2000

Many researchers believe that the amyloid-β peptide is a culprit in the neurodegenerative process of Alzheimer's disease. Indeed, they can marshal good evidence that the fibrillar form of Aβ kills neurons in a petri dish. If this is indeed the cause of AD neurodegeneration, a critical question to answer is how Aβ kills neurons. Bruce Yanker and his colleagues at Harvard suggest that the answer involves Aβ's parent protein, amyloid precursor protein (APP). In the May issue of Nature Neuroscience, they describe experiments that indicate that Aβ cell toxicity is enhanced in the presence of APP, possibly as the result of a direct interaction between the two molecules.

In extracts from cultured rat neurons, they found that fibrillar Aβ (in both its 40 and 42 amino acid forms), but not the nontoxic amorphous form of Aβ, bound to various membrane proteins, among them APP. Fibrillar Aβ did not bind as well to the soluble form of APP as it did to the membrane-bound form. They further found that Aβ was more toxic in cultures of neurons with normal (wildtype) APP than in cultures of neurons from mice lacking a functioning APP gene (APP-null mice). The authors acknowledge that a previous study (White AR et al., 1998) found no difference between Aβ neurotoxicity in APP null and wildtype cultures, but they suggest methodological explanations for this apparent contradiction. "The most straightforward interpretation of our findings is that binding of Aβ to APP resulted in a toxic gain of function, possibly by inducing an APP conformational change that triggered cell death," write the authors.—Hakon Heimer