Presenilin 1 (PS1) levels may indirectly affect amyloid precursor protein (APP) processing and impair memory

Abstract

The P8 line of the senescence accelerated (SAMP8) mice exhibits early loss of memory and premature aging. This loss of memory could be partially reversed by reducing the levels of amyloid precursor protein (APP), a ubiquitous membrane protein that is physiologically processedby site‐specific proteolysis by the endo peptidases called α, β and γ secretases. Cleavage by α‐or β‐secretases followed by γ‐secretase at multiple sites inthe transmembrane region of APP results inthe release of small peptides, Aβ1–40 and Aβ1–42. γ‐secretase is a high molecular weight complex which is composed of presenilin 1 (PS1), mature nicastrin, APH‐1, and Pen‐2. As PS1 has been shown to play a critical role in facilitating γ‐secretase activity as one of its integral components, and mutations in this protein are associated with Familial Alzheimer's Disease (FAD), for this investigation we have cloned it from SAMP8 mouse hippocampus and compared its sequence with other species. Further, changes in the expression of PS1 with age in the hippocampal tissue of SAMP8 were studied. The results showed that PS1 cDNA sequence of SAMP8 is identical to that of normal mouse. However, its expression in the hippocampal tissues of SAMP8 exhibited a decrease when normalized to actin, while CD‐1 mice, a strain that des not exhibit premature memory loss, showed either no loss or a slight increase with age. This reduced amount or mutation(s) in PS1, which may alter the stoichometric balance of the γ‐secretase complex, may be the cause for aberrant or increased processing of APP resulting in Aβ accumulation consequently causing early loss of memory.