Role of tau in the polymerization of peptides from beta-amyloid precursor protein.

The composition of paired helical filaments (PHFs), the intracellular amyloid fibrils that accumulate in the brains of Alzheimer patients, is not completely known. We investigated whether synthetic peptides from beta-amyloid precursor protein (APP) can form PHF-like fibrils. Two peptides formed fibrils morphologically similar to PHFs. The presence of tau protein, a known PHF component, greatly enhanced the numbers of fibrils formed from one peptide, from the C-terminus of APP, and became associated with the fibrils. A tau fragment corresponding to the tubulin-binding region was sufficient to induce fibril formation. Tau did not alter fibril formation by the other peptide, which was from the beta/A4 region of APP. These results raise the possibility that a C-terminal fragment of APP, along with tau, may be involved in PHF formation. Thus the proteolytic processing of APP may generate fragments that contribute to both amyloids and both histopathologic lesions of Alzheimer's disease.

Association of the carboxy-terminus of beta-amyloid protein precursor with Alzheimer paired helical filaments.

We investigated whether a peptide fragment from the C-terminus of beta-amyloid protein precursor is associated with Alzheimer paired helical filaments (PHFs). Antiserum BR188, to the last 20 amino acids of the precursor, did not cross-react with tau protein, known to be in PHFs. It did react with all five pronase-treated PHF preparations assayed by ELISA and immunogold-labelled the same PHF fibrils that a PHF-specific tau antibody labelled. Neither antibody labelled beta/A4 fibrils. These results suggest that a fragment from the C-terminus of beta-amyloid precursor protein copurifies with pronase-treated PHFs and may play a role in their molecular pathogenesis.

The influence of amino acid sequence on the fibrillogenicity and amyloidogenicity of the carboxy-terminus of beta-amyloid precursor protein.

C-APP, a synthetic peptide corresponding to the C-terminal 20 amino acids of beta-amyloid precursor protein, forms amyloid fibrils in vitro. We investigated the effect of altering the C-APP sequence or deleting part of it on its ability to form amyloid fibrils. Substituting any single amino acid in the C-APP sequence with alanine did not prevent the formation of CAPP-like fibrils. Peptides with single or multiple substitutions that included T11, F14, F15, or Q19 showed reduced fibril-forming capacity while those with K1 and/or K13 replaced with alanine or glutamic acid showed enhanced capacity. When P10 or F14 was replaced with alanine, the fibrils were less congophilic than C-APP fibrils. All of the truncated peptides that were able to form fibrils contained at least 9 amino acids from the N-terminus of C-APP or amino acids 7-20 from the C-terminus. However, several peptides that met these criteria, but started at Q3 or contained only 2-4 amino acids C-terminal to P-10, failed to form many or typical fibrils. Peptides that contained the C-APP sequence plus 5-20 adjacent amino acids from the beta-amyloid precursor protein formed fibrils less readily than C-APP and most of the fibrils were not congophilic. The exception was CAPP-30, which formed moderate amounts of congophilic fibrils resembling C-APP fibrils morphologically. Therefore, proteolysis which releases C-APP from these peptides (except CAPP-30) would be predicted to enhance their amyloidogenicity. These results suggest that several features of C-APP peptide may be important in fibril formation. One of these features is the length of the peptide, with lengths of about 10, 20, or 30 amino acids, favoring fibril formation.