Processing of amyloid precursor protein and amyloid peptide neurotoxicity.
Alzheimer's disease is characterized by the presence of two types of lesions in brain: neurofibrillary tangles and senile plaques. Intraneuronal neurofibrillary tangles are made of paired helical filaments containing hyperphosphorylated microtubule associated protein tau. Extracellular senile plaques contain a core of beta-amyloid peptide (Abeta), which is produced by cleavage of the Amyloid Precursor Protein (APP). Among the two catabolic pathways of APP, the amyloidogenic pathway producing Abeta peptides was intensively studied in different cellular models expressing human APP. Differences in APP processing and in toxicity resulting from Abeta accumulation can be observed from one cell type to another. In particular, primary cultures of neurons process APP differently compared with other cultured cells including neuronal cell lines. Neurons accumulate intraneuronal Abeta, which is neurotoxic, and in these cells, APP can be phosphorylated at specific residues. Recent studies suggest that APP phosphorylation can play an important role in its amyloidogenic processing. In addition, protein kinases that phosphorylate APP are also able to phosphorylate the neuronal protein tau. Biochemical analysis of these two proteins in primary cultures of neurons show that phosphorylation of both APP and tau can be a factor linking the two characteristic lesions of Alzheimer's disease.
Nathalie
Pierrot
P
Laboratory of Experimental Pharmacology (FARL), Université catholique de Louvain, 54 Avenue Hippocrate, UCL 54.10, 1200 Brussels, Belgium.
Jean-Noël
Octave
O
D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D006801:Humans; D009474:Neurons / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D014162:Transfection
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor