Alzheimerʼs PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid β-peptide

Guo, Qing; Furukawa, Koichi; Sopher, Bryce L.; Pham, Dao; Xie, Jun; Robinson, Nic; Martin, George M.; Mattson, Mark P.

doi:10.1097/00001756-199612200-00074

Cited by 308 publications

(267 citation statements)

References 6 publications

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“…Moreover, ultrastructural damage to the Golgi apparatus and mitochondria is observed with exposure to ␤-amyloid (Behl et al, 1994a,b). Expression of a presenilin-1 mutation linked to an autosomal dominant form of AD exaggerates calcium responses to carbachol and enhances apoptotic vulnerability to ␤-amyloid (Guo et al, 1996). Thus, familial forms of AD associated with presenilin-1 or ␤-amyloid mutations and sporadic forms of AD with mitochondrial dysfunction and mtDNA defects seem to exhibit similar calcium homeostasis disturbances that may lead to a common AD neuropathology.…”

Section: Discussionmentioning

confidence: 99%

Calcium Homeostasis and Reactive Oxygen Species Production in Cells Transformed by Mitochondria from Individuals with Sporadic Alzheimer’s Disease

Sheehan

Swerdlow

Miller³

et al. 1997

J. Neurosci.

241

140

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Alzheimer's disease (AD) is associated with defects in mitochondrial function. Mitochondrial-based disturbances in calcium homeostasis, reactive oxygen species (ROS) generation, and amyloid metabolism have been implicated in the pathophysiology of sporadic AD. The cellular consequences of mitochondrial dysfunction, however, are not known. To examine these consequences, mitochondrially transformed cells (cybrids) were created from AD patients or disease-free controls. Mitochondria from platelets were fused to 0 cells created by depleting the human neuroblastoma line SH-SY5Y of its mitochondrial DNA (mtDNA). AD cybrids demonstrated a 52% decrease in electron transport chain (ETC) complex IV activity but no difference in complex I activity compared with control cybrids or SH-SY5Y cells. This mitochondrial dysfunction suggests a transferable mtDNA defect associated with AD. ROS generation was elevated in the AD cybrids. AD cybrids also displayed an increased basal cytosolic calcium concentration and enhanced sensitivity to inositol-1,4,5-triphosphate (InsP 3 )-mediated release. Furthermore, they recovered more slowly from an elevation in cytosolic calcium induced by the InsP 3 agonist carbachol. Mitochondrial calcium buffering plays a major role after this type of perturbation. ␤-amyloid (25-35) peptide delayed the initiation of calcium recovery to a carbachol challenge and slowed the recovery rate. Nerve growth factor reduced the carbachol-induced maximum and moderated the recovery kinetics. Succinate increased ETC activity and partially restored the AD cybrid recovery rate. These subtle alterations in calcium homeostasis and ROS generation might lead to increased susceptibility to cell death under circumstances not ordinarily toxic.

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Section: Discussionmentioning

confidence: 99%

Calcium Homeostasis and Reactive Oxygen Species Production in Cells Transformed by Mitochondria from Individuals with Sporadic Alzheimer’s Disease

Sheehan

Swerdlow

Miller³

et al. 1997

J. Neurosci.

241

140

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“…Additional evidence supports a role for the presenilins in regulating ER calcium levels. First, thapsigargin-and ionophore-releasable calcium pools are increased in several systems harboring PS1 mutations, including PC12 cells (Guo et al, 1996), fibroblasts from human FAD patients (Gibson et al, 1996) and mutant PS1 knock-in animals . Second, in brain slices from transgenic animals expressing PS1 mutations, electrophysiological abnormalities are present, including enhanced long-term potentiation (LTP) and increased after-hyperpolarization, and both alterations can be attributed to increased release of ER calcium (Barrow et al, 2000;Parent et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Subcellular Mechanisms of Presenilin-Mediated Enhancement of Calcium Signaling

Leissring

LaFerla

Callamaras

et al. 2001

Neurobiology of Disease

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Mutations in presenilin-1 (PS1), the leading cause of early-onset, autosomal-dominant familial Alzheimer's disease (FAD), enhance calcium signaling mediated by inositol 1,4,5-trisphosphate (IP 3 ). To elucidate the subcellular mechanisms underlying this enhancement, we used high resolution linescanning confocal microscopy to image elementary calcium release events ("puffs") in Xenopus oocytes expressing wild-type or mutant PS1. Here we report that mutant PS1-rendered puffs more sensitive to IP 3 and increased both the magnitude and the rate of calcium release during each event. These effects were not attributable to quantitative changes in the levels of IP 3 receptors or their distribution on the ER, but were instead associated with an abnormal elevation of ER calcium stores. Together, our results suggest that the effects of mutant PS1 on calcium signaling are manifested predominantly at the level of the regulation of calcium stores rather than via perturbations in the numbers or activity of IP 3 -activated calcium release channels.

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“…[51][52][53] An increased expression of the ryanodine receptor (RYR), particularly the RYR3 isoform, 53 is one cause for this hypersensitivity of the internal release mechanism. 52,[54][55][56] The increase in RYR expression results in a greater sensitivity to Ca 2+ elevations during normal synaptic transmission.…”

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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Alzheimerʼs PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid β-peptide

Cited by 308 publications

References 6 publications

Calcium Homeostasis and Reactive Oxygen Species Production in Cells Transformed by Mitochondria from Individuals with Sporadic Alzheimer’s Disease

Calcium Homeostasis and Reactive Oxygen Species Production in Cells Transformed by Mitochondria from Individuals with Sporadic Alzheimer’s Disease

Subcellular Mechanisms of Presenilin-Mediated Enhancement of Calcium Signaling

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

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