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 alpha- or 
beta-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 gamma-secretase at multiple sites in 
the transmembrane region, releasing small peptides, Abeta(1-40) and Abeta(1-42), 
the major components of AD-associated amyloid fibrils. gamma-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 
gamma-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 gamma-secretase complex, may be the cause of 
aberrant or increased processing of APP, resulting in Abeta accumulation leading 
to loss of memory.