A βPP peptide carboxyl-terminal to Aβ is neurotoxic

Extracellular A beta-amyloid and intraneuronal paired helical filaments (PHFs) composed of tau protein are the neuropathological hallmark of Alzheimer's disease. A beta is a 39- to 43-residue peptide derived by cleavage of a 695- to 770-amino-acid membrane-associate glycoprotein (termed beta-protein precursor, beta PP). Following the observation that an antiserum to an epitope located between residues 713 and 723 of beta PP770 (ie, the transmembrane region of the beta PP distal to A beta) labels PHFs and that a synthetic peptide homologous to residues 713 to 730 of beta PP770 (beta PP713-730) is highly fibrillogenic and interacts with tau in vitro, it has been hypothesized that beta PP fragments other than A beta 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 beta PP713-730. Cultures were prepared from rat hippocampus on embryonic day 17 and incubated with the peptide at 2.5 to 30 mu mol/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 mu mol/L beta PP713-730 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 beta PP sequences other than A beta may play a role in nerve cell degeneration in Alzheimer's disease.