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

Abstract

SUMMARYSenescence-accelerated mice (SAMP8) serve as a model for Alzheimerʼs 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 α-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 (ʻAICDʼ-APP intracellular domain). These are subsequently cleaved by γ-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. γ-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 γ-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 γ-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. THE JOURNAL OF EXPERIMENTAL BIOLOGY 495Increase in PS1 may cause memory loss of other species, including the house mouse, in order to locate any mutations that may be presented in the SAMP8 mouse sequence. Many mutations that are linked to FAD occur in human PS1 but only a few occur in APP. Therefore, even a single change in the PS1 sequence in SAMP8 mouse may explain the cause of its loss of memory at an earlier age. While no change in sequence was noticed in the SAMP8 PS1, protein expression increased with age in these mice, providing a possible mechanism for the increase in hippocampal Aβ. MATERIALS AND METHODS MaterialsAll fine chemicals were obtained from Sigma Chemical Company, St Louis, MO, USA. Sequencing grade [ 35 S]ATP was obtained from ICN Biomedicals, Costa Mesa, CA, USA. PVDF membranes for western blotting were supplied by BioRad Laboratories, Hercules, CA, USA. Lipofectamine was supplied by BRL-GIBCO, Gaithersburg, MD, USA. Antibody that detects the PS1 holoprotein was obtained from Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA. GAPDH antibodies are from Calbiochem, San Diego, CA, USA. 4-12% Bis-tris gels with MES buffer were from Invitrogen, Carlsbad, CA, USA. Senescence-accelerated P8 line (SAMP8) and CD-1 mice were from our in-house colonies. Hippocampal tissues were dissected from ...

Age-Dependent Impairment of Spine Morphology and Synaptic Plasticity in Hippocampal CA1 Neurons of a Presenilin 1 Transgenic Mouse Model of Alzheimer's Disease

“…The data also shed light on the fact that the overexpression of human PS1 triggers synaptic dysfunction at older ages. Recently, Kumar et al (2009) reported that PS1 expression increased with age in senescence-accelerated mice, which might serve as a model for AD. It has also been shown that PS1 is highly expressed both during normal aging and in brains developing sporadic AD (Miller et al, 2008).…”

“…In addition, wild-type PS1 overexpression alone, which does not lead to A␤ hypersecretion, has never been reported to have major pathological manifestations in young animals. Although the long term effects of wild-type human PS1 overexpression have never been analyzed, a growing body of evidence suggests that PS1 expression level during both normal and pathological aging may play an important role (Miller et al, 2008;Kumar et al, 2009).…”

Effects of ZSET1446/ST101 on Cognitive Deficits and Amyloid ^|^beta; Deposition in the Senescence Accelerated Prone Mouse Brain

“…The nucleotide sequence of APP in the hippocampus of SAMP8 does not have mutations similar to those that have been reported in human familial AD (4). Moreover, the SAMP8 PS1 cDNA sequence is identical to that of normal mice (5). The SAMP8 is characterized by an earlier onset of deficits in learning and memory than the normally aging mice, SAMR, in several tasks such as active and passive avoidance, Tmaze, and water maze tasks (6 -8).…”

Senescence-Accelerated Mice P8: A Tool to Study Brain Aging and Alzheimer's Disease in a Mouse Model

“…PS1 has been shown to play a critical role in facilitating γ-secretase activity, and levels of γ-secretase modulate the Aβ 42 /Aβ 40 ratio, which is important for plaque formation [80]. Moreover, mutations in this protein are associated with familial AD (FAD).…”