Alzheimer's Disease Research Today is a free monthly online journal that collates and summarizes the latest research about Alzheimer's Disease, including details on diagnosis, memory loss, heredity, treatment, medication.

Linear patterns of Alzheimer's disease mutations along alpha-helices of presenilins as a tool for PS-1 model construction.

Jozwiak K, Zekanowski C, Filipek S

International Institute of Molecular and Cell Biology, Warsaw, Poland.

We performed an analysis of mutation patterns in all 10 hydrophobic regions (HRs) of presenilin-1 (PS-1) and PS-2 using a recent database of Alzheimer's disease (AD) mutations. The linear patterns were confirmed and extended to areas spanning as many as three faces of a given HR. The complementary areas of residues free of AD mutations were identified based on the location of non-pathogenic polymorphisms and PS-1 versus PS-2 amino acid discordances. Taking into account the location of areas of AD mutations and mutation-free areas/regions, we proposed a preliminary model of PS-1 structure using a general stick-out-mutation rule. To build a molecular structure of PS-1 and preserve features of the preliminary model, we used bacteriorhodopsin template in homology/comparative modelling. Two molecular models were built differing in the location of C-terminal fragment helices. The models properly distinguish residues belonging to AD-affected sites and non-pathogenic areas, and may be used for classification purposes. They also comply with experimental results, such as differences in accessibility of the catalytic residues in uncleaved PS-1, and binding of PEN-2 by the PS-1 NF motif.

Published 22 August 2006 in J Neurochem, 98(5): 1560-72.
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