γ-Secretase Activity of Presenilin 1 Regulates Acetylcholine Muscarinic Receptor-mediated Signal Transduction

Abstract

Familial Alzheimer's disease (FAD) presenilin 1 (PS1) mutations give enhanced calcium responses upon different stimuli, attenuated capacitative calcium entry, an increased sensitivity of cells to undergo apoptosis, and increased ␥-secretase activity. We previously showed that the FAD mutation causing an exon 9 deletion in PS1 results in enhanced basal phospholipase C (PLC) activity (Cedazo-Minguez, A., Popescu, B. O., Ankarcrona, M., Nishimura, T., and Cowburn, R. ] i responses to levels found in PS1 D257A or PS1 D385N dominant negative cells. Our findings suggest that PS1 can regulate PLC activity and that this function is ␥-secretase activity-dependent.Mutations in genes encoding presenilins are responsible for the majority of early onset familial Alzheimer's disease (FAD) 1 cases. Presenilins are multipass membrane proteins that form a high molecular complex with other binding partners (Aph-1, Pen-2, and Nicastrin) so as to execute an intramembraneous proteolytic activity known as ␥-secretase cleavage (1). The ␥-secretase complex cleaves several integral membrane proteins; of particular interest for AD pathogenesis is the ␤-amyloid precursor protein (APP), which is processed to different peptide fragments (2), including ␤-amyloid (A␤) and the APPintracellular domain (AICD). Although A␤ is secreted in the extracellular milieu, the AICD was found to translocate to the nucleus and form a transcriptively active complex with the nuclear adaptor protein Fe65, in a manner similar to the intracellular domain of Notch (3). The releases of both A␤ and AICD from the C-terminal fragment of APP are dependent on ␥-secretase activity (4, 5).Different FAD mutations in the presenilin 1 (PS1) and presenilin 2 (PS2) genes were shown to increase production of the longer and more fibrillogenic forms of A␤ (6). There is a wealth of data showing A␤ to be neurotoxic in various experimental paradigms (7). Another pathogenic pathway by which mutated PS1 triggers neurodegeneration is the sensitization of cells to undergo death by apoptosis (8), although there is as yet no proof to link the proapoptotic effects of mutant PS1 to increased A␤ secretion. Under stress conditions, the cells expressing mutant PS1 show increased caspase-3, caspase-12, and calpain activation (9, 10); high oxyradical production; and perturbed calcium homeostasis (11). Moreover, FAD PS1 mutants were shown to disrupt calcium signaling not only in response to toxic stimuli but also to the physiological signals of inositol 1,4,5-trisphosphate (IP 3 ), bradykinin, and glutamate (12, 13). The fact that all analyzed FAD PS1 mutations have been found to alter calcium signaling could be of relevance to AD pathogenesis, especially because deregulation of [Ca 2ϩ ] i is also a constant finding in cells from AD patients and in AD experimental models (14). Increased [Ca 2ϩ ] i can also result in enhanced A␤ generation (15), whereas in turn cells treated with A␤ show increased [Ca 2ϩ ] i (16). In contrast secreted APP stabilizes calcium homeostasis (17).A large proportio...

PS2 mutation increases neuronal cell vulnerability to neurotoxicants through activation of caspase‐3 by enhancing of ryanodine receptor‐mediated calcium release

“…This result is in accord with speculations by other investigators who have reported that the perturbation of intracellular calcium homeostasis through RyR may be critical for mutant PS1-induced PC12 and cortical neuronal cell death in response to various stimuli and conditions (9,(16)(17)(18). Similarly, the increased vulnerability of the cells by the elevated intracellular calcium from RyR was also found in the SH-SY5Y neuroblastoma cells, as well as neurons carrying mutant PS1 (36,37). Schneider et al (38) also reported that neuronal cell death of PS2 mutant mice was also prevented with dantrolene.…”

Presenilin 1 Interacts with Acetylcholinesterase and Alters Its Enzymatic Activity and Glycosylation

“…A role for PS1 in the regulation of muscarinic receptormediated signal transduction has also been suggested (55). Here, we show the cell surface colocalization of PS1 and AChE in COS-7 cells in addition to their predominant perinuclear colocalization.…”

Blood-brain barrier alterations in ageing and dementia

“…The ApoE genotype is a known factor for AD [92], and inflammation [93], vascular factors [94], oxidative stress and synaptic dysfunction [95], alterations in cell signalling [96] and sensitization to cell death [97] all appear to be important pathogenic mechanisms. Many of these factors are encountered in other dementia types, mainly in VD, therefore giving rationale for the concept that most of the dementia cases in fact have a mixed origin [54].…”