Mutant Presenilins Disturb Neuronal Calcium Homeostasis in the Brain of Transgenic Mice, Decreasing the Threshold for Excitotoxicity and Facilitating Long-term Potentiation

Schneider, Ilka; Reversé, Delphine; Dewachter, Ilse; Ris, Laurence; Caluwaerts, Nathalie; Kuipéri, Cuno; Gilis, Martine; Geerts, Hugo; Kretzschmar, Hans A.; Godaux, Emile; Moechars, Dieder; Leuven, Fred Van; Herms, Jochen

doi:10.1074/jbc.m010977200

Cited by 123 publications

(81 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We observed that APP/PS1KI mice with only one mutant PS1 allele, wildtype and PS1KI mice showed a normal LTP pattern at 6 months. Previously, synaptic transmission and hippocampal LTP has been shown to be already altered in transgenic mice overexpressing only FAD linked PS1 mutations [32,39]. Therefore, the normal LTP pattern in PS1KI control mice could be due to low expression levels of endogenous murine PS1.…”

Section: Discussionmentioning

confidence: 99%

APP/PS1KI bigenic mice develop early synaptic deficits and hippocampus atrophy

et al. 2009

View full text Add to dashboard Cite

Abeta accumulation has an important function in the etiology of Alzheimer's disease (AD) with its typical clinical symptoms, like memory impairment and changes in personality. However, the mode of this toxic activity is still a matter of scientific debate. We used the APP/PS1KI mouse model for AD, because it is the only model so far which develops 50% hippocampal CA1 neuron loss at the age of 1 year. Previously, we have shown that this model develops severe learning deficits occurring much earlier at the age of 6 months. This observation prompted us to study the anatomical and cellular basis at this time point in more detail. In the current report, we observed that at 6 months of age there is already a 33% CA1 neuron loss and an 18% atrophy of the hippocampus, together with a drastic reduction of long-term potentiation and disrupted paired pulse facilitation. Interestingly, at 4 months of age, there was no long-term potentiation deficit in CA1. This was accompanied by reduced levels of pre-and post-synaptic markers. We also observed that intraneuronal and total amount of different Abeta peptides including N-modified, fibrillar and oligomeric Abeta species increased and coincided well with CA1 neuron loss. Overall, these data provide the basis for the observed robust working memory deficits in this mouse model for AD at 6 months of age.

show abstract

Section: Discussionmentioning

confidence: 99%

APP/PS1KI bigenic mice develop early synaptic deficits and hippocampus atrophy

et al. 2009

View full text Add to dashboard Cite

show abstract

“…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).…”

mentioning

confidence: 99%

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

Popescu

Cedazo-Minguez

Benedikz

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

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...

show abstract

“…5 and 6). Also, AD-associated mutations of presenilin-1 disrupt calcium homeostasis and increase susceptibility to ER stress and apoptosis (7)(8)(9)(10)(11)(12), whereas wild-type presenilin-1 is necessary for cellular responses to ER stress (13). Furthermore, an AD-associated splice variant of presenilin-2 increases vulnerability to ER stress (14).…”

mentioning

confidence: 99%

Central Role of Glycogen Synthase Kinase-3β in Endoplasmic Reticulum Stress-induced Caspase-3 Activation

Lee

Sarno

Jope

2002

Journal of Biological Chemistry

255

240

View full text Add to dashboard Cite

Stress of the endoplasmic reticulum (ER), which is associated with many neurodegenerative conditions, can lead to the elimination of affected cells by apoptosis through only partially understood mechanisms. Thapsigargin, which causes ER stress by inhibiting the ER Ca 2؉ -ATPase, was found to not only activate the apoptosis effector caspase-3 but also to cause a large and prolonged increase in the activity of glycogen synthase kinase-3␤ (GSK3␤). Activation of GSK3␤ was obligatory for thapsigargin-induced activation of caspase-3, because inhibition of GSK3␤ by expression of dominantnegative GSK3␤ or by the GSK3␤ inhibitor lithium blocked caspase-3 activation. Thapsigargin treatment activated GSK3␤ by inducing dephosphorylation of phospho-Ser-9 of GSK3␤, a phosphorylation that normally maintains GSK3␤ inactivated. Caspase-3 activation induced by thapsigargin was blocked by increasing the phosphorylation of Ser-9-GSK3␤ with insulin-like growth factor-1 or with the phosphatase inhibitors okadaic acid and calyculin A, but the calcineurin inhibitors FK506 and cyclosporin A were ineffective. Insulin-like growth factor-1, okadaic acid, calyculin A, and lithium also protected cells from two other inducers of ER stress, tunicamycin and brefeldin A. Thus, ER stress activates GSK3␤ through dephosphorylation of phospho-Ser-9, a prerequisite for caspase-3 activation, and this process is amenable to pharmacological intervention.

show abstract

Mutant Presenilins Disturb Neuronal Calcium Homeostasis in the Brain of Transgenic Mice, Decreasing the Threshold for Excitotoxicity and Facilitating Long-term Potentiation

Cited by 123 publications

References 50 publications

APP/PS1KI bigenic mice develop early synaptic deficits and hippocampus atrophy

APP/PS1KI bigenic mice develop early synaptic deficits and hippocampus atrophy

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

Central Role of Glycogen Synthase Kinase-3β in Endoplasmic Reticulum Stress-induced Caspase-3 Activation

Contact Info

Product

Resources

About