βPP and tau interaction: A possible link between amyloid and neurofibrillary tangles in Alzheimer's disease

Extracellular deposition of amyloid fibrils and intraneuronal accumulation of paired helical filaments (PHFs) are the neuropathological hallmarks of Alzheimer's disease. The major constituent of amyloid fibrils is a 39- to 43- residue peptide (termed Aβ), which is derived from a 695- to 770-amino-acid precursor protein (termed βPP). The main component of PHFs identified so far is the microtubule-associated protein tau. Yet, there is no direct evidence of interconnection between these two pathological states. We report here that antibodies to an epitope located between residues 713 and 723 of βPP₇₇₀ (ie, the transmembrane region of βPP distal to Aβ) consistently labeled PHFs in the brain of Alzheimer patients. Solid phase immunoassay showed that a peptide homologous to residues 713 to 730 of βPP₇₇₀ bound tau proteins. This βPP peptide spontaneously formed fibrils in vitro and, in the presence of tau, generated dense fibrillary assemblies containing both molecules. These data suggest that βPP or βPP fragments containing the tau binding site are involved in the pathogenesis of PHFs in Alzheimer's disease.