A pilot proteomic study of amyloid precursor interactors in Alzheimer's disease (original) (raw)

2005, Annals of Neurology

Several approaches have been used in an effort to identify proteins that interact with β-amyloid precursor protein (APP). However, few studies have addressed the identification of proteins associated with APP in brain tissue from patients with Alzheimer's disease. We report the results of a pilot proteomic study performed on complexes immunoprecipitated with APP in brain samples of patients with Alzheimer's disease and normal control subjects. The 21 proteins identified could be grouped into five functional classes: molecular chaperones, cytoskeletal and structural proteins, proteins involved in trafficking, adaptors, and enzymes. Among the proteins identified, six had been reported previously as direct, indirect, or genetically inferred APP interactors. The other 15 proteins immunoprecipitated with APP were novel potential partners. We confirmed the APP interaction by Western blotting and coimmunolocalization in brain tissues, for 5 of the 21 interactors. In agreement with previous studies, our results are compatible with an involvement of APP in axonal transport and vesicular trafficking, and with a potential association of APP with cellular protein folding/protein degradation systems. Alzheimer's disease (AD), a progressive dementia affecting approximately 10% of people older than 65 years, is characterized by the accumulation of amyloid plaques, neurofibrillary tangles, and the progressive loss of synapses and neurons in the brain. 1-3 The major proteinaceous component of amyloid plaques is amyloid-β peptide (Aβ), a variably sized (typically 40-42 residues) peptide derived from the amyloid precursor protein (APP). APP is an integral membrane protein whose transmembrane region contains the carboxyterminal portion of the Aβ peptide. 4 Proteolytic processing by α, β, and γ secretases causes the poorly soluble Aβ1-42 (as well as Aβ 1-40), the soluble p3 peptide, and a 99-amino acid carboxyterminal fragment, among other cleavage products. 5 The cytosolic region has a caspase recognition site at Asp 664 that generates a cytotoxic 31-amino acid C-terminal fragment, C31.