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First published online January 30, 2009
Journal of Experimental Biology 212, 494-498 (2009)
Published by The Company of Biologists 2009
doi: 10.1242/jeb.022780

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Increase in Presenilin 1 (PS1) levels in senescence-accelerated mice (SAMP8) may indirectly impair memory by affecting amyloid precursor protein (APP) processing

Vijaya B. Kumar^*, Mark Franko, William A. Banks, Pranav Kasinadhuni, Susan A. Farr, Kamlesh Vyas, Veena Choudhuri and John E. Morley

Division of Geriatric Research, Education and Clinical Center, VA Medical Center, St Louis, MO 63125, USA and St Louis University Health Sciences Center, St Louis, MO 63104, USA

^* Author for correspondence (e-mail: kumar{at}slu.edu)

Accepted 7 October 2008

Senescence-accelerated mice (SAMP8) serve as a model for Alzheimer's disease (AD) as they exhibit early loss of memory and increased amyloid precursor protein (APP) expression. APP is a ubiquitous membrane protein that is physiologically processed by site-specific proteolysis firstly by - or β-secretases, releasing a large fragment called APP_S that contains most of the extracellular sequences of APP, a small extracellular stub, the transmembrane region and the cytoplasmic tail of APP (`AICD'-APP intracellular domain). These are subsequently cleaved by -secretase at multiple sites in the transmembrane region, releasing small peptides, Aβ_1-40 and Aβ_1-42, the major components of AD-associated amyloid fibrils. -secretase is a high-molecular-mass complex composed of presenilin-1 (PS1), nicastrin, APH-1 and Pen-2. As PS1 has been shown to play a critical role in facilitating -secretase activity, and mutations in this protein are associated with familial AD (FAD), we have cloned it from SAMP8 mouse hippocampus and compared its sequence with those of other species. Furthermore, changes in the expression of PS1 with age in the hippocampal tissue of SAMP8 were studied. The results showed that the SAMP8 PS1 cDNA sequence is identical to that of normal mice. However, its expression in the hippocampus of SAMP8 exhibited an increase, while CD-1 mice, a strain that does not exhibit premature memory loss, showed no change with age. An increased amount or mutation(s) in PS1, which alters the stoichiometric balance of the -secretase complex, may be the cause of aberrant or increased processing of APP, resulting in Aβ accumulation leading to loss of memory.

Key words: aging, amyloid, memory, presenilin, scenecence

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