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Pin-pointing APP Processing

Max-Delbrueck-Center for Molecular Medicine, D-13125, Berlin, Germany

SUMMARY

The neuropathological hallmarks of Alzheimer Disease (AD) are neurofibrillar tangles composed of tau protein and neuritic plaques containing the amyloid ß-peptide (Aß) that is derived from proteolytic processing of the amyloid precursor protein (APP). Proline is the sole -imino acid in nature's repertoire and, therefore, the only peptide residue that can exist in cis or trans conformation. When phosphorylated on serine or threonine found adjacent to proline, both tau and APP undergo conformational changes that promote the formation of tangles and, in the case of APP, processing to Aß. Now, new findings on the role of the Pin1, a peptidyl-prolyl cis/trans isomerase (PPIase) that catalyzes rotation of the protein backbone at proline residues, appear to indicate that Pin1 binds to and isomerizes distinct proline residues located in the commonly found phospho-Ser/Thr-Pro motif within APP to detangle APP fibers.Interestingly, the expression of Pin1 is decreased in degenerating neurons of AD patients and causes age-dependent neurodegeneration when deleted in mice.