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(American Journal of Pathology. 1999;154:1001-1007.)
© 1999 American Society for Investigative Pathology

Short Communication

A ßPP Peptide Carboxyl-Terminal to Aß Is Neurotoxic

Gabriella Marcon* , Giorgio Giaccone* , Barbara Canciani* , Laura Cajola* , Giacomina Rossi* , Luca De Gioia{dagger} , Mario Salmona{dagger} , Orso Bugiani* and Fabrizio Tagliavini*

From the Division of Neuropathology,* Istituto Nazionale Neurologico Carlo Besta, and the Istituto di Ricerche Farmacologiche Mario Negri,{dagger} Milano, Italy

Extracellular Aß-amyloid and intraneuronal paired helical filaments (PHFs) composed of tau protein are the neuropathological hallmark of Alzheimer's disease. Aß is a 39- to 43-residue peptide derived by cleavage of a 695- to 770-amino-acid membrane-associate glycoprotein (termed ß-protein precursor, ßPP). Following the observation that an antiserum to an epitope located between residues 713 and 723 of ßPP770 (ie, the transmembrane region of the ßPP distal to Aß) labels PHFs and that a synthetic peptide homologous to residues 713 to 730 of ßPP770 (ßPP713–730) is highly fibrillogenic and interacts with tau in vitro, it has been hypothesized that ßPP fragments other than Aß may feature in the pathogenesis of Alzheimer's disease concurring with neuronal degeneration. To investigate this issue, we have analyzed the effects of the exposure of primary neuronal cultures to the synthetic peptide ßPP713–730. Cultures were prepared from rat hippocampus on embryonic day 17 and incubated with the peptide at 2.5 to 30 µmol/L concentration for 1 to 4 days. Cell viability was compared with that of control cultures exposed to a scrambled sequence of the peptide. A 4-day exposure to 20 µmol/L ßPP713–730 resulted in almost complete neuronal loss, whereas no changes were observed with the scrambled peptide. Degenerating neurons showed DNA fragmentation by agarose gel electrophoresis and apoptotic changes by light and electron microscopy. These findings support the view that ßPP sequences other than Aß may play a role in nerve cell degeneration in Alzheimer's disease.




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Copyright © 1999 by the American Society for Investigative Pathology.