Introduction and Overview

Khachaturian, Zaven S.

doi:10.1111/j.1749-6632.1989.tb12485.x

Cited by 175 publications

(51 citation statements)

References 6 publications

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“…As such, the apparent role of calcium as a key regulator in this process may be of importance. Calcium has been implicated in aging and in Alzheimer disease (e.g., [32][33][34][35][36][37]. Targeting calcium for potential therapies in AP amyloidosis is therefore worth consideration.…”

Section: Discussionmentioning

confidence: 99%

Calcium regulates processing of the Alzheimer amyloid protein precursor in a protein kinase C-independent manner.

Buxbaum

Ruefli

Parker

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

167

140

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Various first messengers linked to phospholipase C, including acetylcholine and interleukin 1, regulate the production both of the secreted form of the amyloid protein precursor (APP) and of amyloid a-protein. We have now identified intracellular signals which are responsible for mediating these effects. We show that activation of phospholipase C may affect APP processing by either of two pathways, one involving an increase in protein kinase C and the other an increase in cytoplasmic calcium levels. The effects ofcalcium on APP processing appear to be independent of protein kinase C activation. The observed effects of calcium on APP processing may be of therapeutic utility.Alzheimer disease is characterized by distinct neuropathological lesions, including intracellular neurofibrillary tangles, extracellular parenchymal and cerebrovascular amyloid deposits; and selective cell death that particularly affects cholinergic neurons in the basal forebrain (1). The principal component of parenchymal amyloid plaque cores and cerebrovascular amyloid is the amyloid (3-protein (A(3) (2-4). It has been shown that this -4-kDa protein is produced by various cultured cells (5-7), including transfected cells stably expressing the amyloid protein precursor (APP), from which AB is derived (8)(9)(10)(11)(12)(13)(14).During the past few years, a variety of evidence has emerged indicating that the processing of APP is regulated by signal transduction pathways. Thus, phorbol esters (activators of protein kinase C) and okadaic acid (an inhibitor of protein phosphatases 1 and 2A) increase APP metabolism and secretion (15-18). More recently, it has been shown that first messengers known to activate the phospholipase C/protein kinase C cascade increase the secretion of APP (17,19). It was also shown that the formation of a peptide with properties similar to those of Af was decreased by phorbol esters, by okadaic acid, by direct activators of phospholipase C, and by first messengers that activate phospholipase C (20-22). However, activation of phospholipase C not only activates protein kinase C (through the formation ofdiacylglycerol) but also increases cytoplasmic calcium (through the action of inositol 1,4,5-trisphosphate, IP3). For this reason, we undertook an investigation to determine whether the IP3/calcium limb of this pathway might, like the diacylglycerol/protein kinase C limb, affect APP processing. MATERIALS AND METHODSCell culture conditions and the sources of analytical reagents have been described (17,20 Pulse-chase labeling of cells was carried out on confluent cell monolayers in six-well culture dishes (Corning) with 1 ml of methionine-free Dulbecco's modified Eagle's medium (DMEM) supplemented with 1 mCi (37 MBq) of [35S]methionine/cysteine (EXPRE35S35S; NEN). Metabolic labeling was carried out for 2 hr, followed by a chase period of 2 hr. The chase was initiated by replacing the labeling medium with DMEM containing 0.2 mM unlabeled methionine. Two minutes after the start of the chase, the indicated test compounds ...

show abstract

Section: Discussionmentioning

confidence: 99%

Calcium regulates processing of the Alzheimer amyloid protein precursor in a protein kinase C-independent manner.

Buxbaum

Ruefli

Parker

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

167

140

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“…The “Ca 2+ hypothesis of AD” states that deranged Ca 2+ signaling plays an important role in AD pathogenesis [17, 18]. Interestingly, many FAD mutations in PSs result in deranged Ca 2+ signaling (reviewed in [18, 19]).…”

Section: Introductionmentioning

confidence: 99%

Familial Alzheimer's Disease Mutations in Presenilins: Effects on Endoplasmic Reticulum Calcium Homeostasis and Correlation with Clinical Phenotypes

Nelson

Supnet

Liu

et al. 2010

JAD

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Mutations in presenilins (PS1 and PS2) are responsible for approximately 40% of all early onset familial Alzheimer’s disease (FAD) monogenic cases. Presenilins (PSs) function as the catalytic subunit of γ-secretase and support cleavage of the amyloid precursor protein (APP). We previously discovered that PSs also function as passive endoplasmic reticulum (ER) calcium (Ca2+) leak channels and that most FAD mutations in PSs affected their ER Ca2+ leak function. To further validate the relevance of our findings to human disease, we here performed Ca2+ imaging experiments with lymphoblasts established from FAD patients. We discovered that most FAD mutations in PSs disrupted ER Ca2+ leak function and resulted in increased ER Ca2+ pool in human lymphoblasts. However, we found that a subset of PS1 FAD mutants supported ER Ca2+ leak activity, as ER Ca2+ pool was unaffected in lymphoblasts. Most of the “functional” mutations for ER Ca2+ leak were clustered in the exon 8–9 area of PSEN1 gene and segregated with the cotton wool plaques and spastic paraparesis (CWP/SP) clinical phenotype occasionally observed in PS1 FAD patients. Our findings with the “functional” and “non-functional” PS1 FAD mutants were confirmed in Ca2+ rescue experiments with PS double-knockout (DKO) mouse embryonic fibroblasts. Based on the combined effects of the PS1 FAD mutations on ER Ca2+ leak and γ-secretase activities we propose a model that explains the heterogeneity observed in FAD. The proposed model has implications for understanding the pathogenesis of both familial and sporadic AD.

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“…[39][40][41][42] When Ca 2+ is measured in the spines and dendrites of cortical pyramidal neurons of transgenic mice, there was a higher than normal resting level in those neurons located close to amyloid deposits. 43 Similarly, the resting level of Ca 2+ in the cortical neurons of 3xTg-AD animals was 247 nmol/L, which was twice that found in the non-Tg controls (110 nmol/L).…”

Section: Bipolar Disordermentioning

confidence: 99%

Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia

Berridge

2013

Prion

181

129

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Introduction and Overview

Cited by 175 publications

References 6 publications

Calcium regulates processing of the Alzheimer amyloid protein precursor in a protein kinase C-independent manner.

Calcium regulates processing of the Alzheimer amyloid protein precursor in a protein kinase C-independent manner.

Familial Alzheimer's Disease Mutations in Presenilins: Effects on Endoplasmic Reticulum Calcium Homeostasis and Correlation with Clinical Phenotypes

Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia

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