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Role of tau in the polymerization of peptides from beta-amyloid precursor protein
C B Caputo1, L A Sygowski, C W Scott
1Pharmacology Department, ICI Americas, Wilmington, DE 19897.
Abstract:
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.
Insights
Alzheimer's disease paired helical filaments (PHFs) may involve a C-terminal APP fragment and tau protein. This study shows synthetic APP peptides can form PHF-like structures, with tau enhancing fibril formation.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Paired helical filaments (PHFs) are key intracellular lesions in Alzheimer's disease brains.
- The precise composition of PHFs, particularly the role of amyloid precursor protein (APP) fragments, remains incompletely understood.
Purpose of the Study:
- To investigate if synthetic peptides derived from APP can self-assemble into PHF-like fibrils.
- To determine the influence of tau protein on the fibril formation of APP-derived peptides.
Main Methods:
- Synthesis of peptides from different regions of APP (beta/A4 and C-terminus).
- Incubation of synthetic peptides with and without tau protein or tau fragments.
- Morphological analysis of formed fibrils using techniques like electron microscopy (implied).
Main Results:
- Two synthetic APP peptides formed fibrils morphologically resembling PHFs.
- Tau protein significantly enhanced fibril formation from the C-terminal APP peptide and co-localized with these fibrils.
- A tau fragment containing the tubulin-binding region was sufficient to induce fibril formation.
- Tau did not affect fibril formation by the beta/A4 region APP peptide.
Conclusions:
- A C-terminal fragment of APP, in conjunction with tau protein, may play a role in the formation of PHFs.
- Proteolytic processing of APP could generate fragments contributing to both amyloid plaques and neurofibrillary tangles in Alzheimer's disease.