A βPP Peptide Carboxyl-Terminal to Aβ Is Neurotoxic

Extracellular Aβ-amyloid and intraneuronal paired helical filaments (PHFs) composed of tau protein are the neuropathological hallmark of Alzheimer's disease. Aβ is a 39- to 43-residue peptide derived by cleavage of a 695- to 770-amino-acid membrane-associate glycoprotein (termed β-protein precursor, βPP). Following the observation that an antiserum to an epitope located between residues 713 and 723 of βPP 770 (ie, the transmembrane region of the βPP distal to Aβ) labels PHFs and that a synthetic peptide homologous to residues 713 to 730 of βPP 770 (βPP713–730) is highly fibrillogenic and interacts with tau in vitro, it has been hypothesized that βPP fragments other than Aβ 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 βPP713–730. 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 βPP713–730 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 βPP sequences other than Aβ may play a role in nerve cell degeneration in Alzheimer's disease.