Functional Phenotype in Transgenic Mice Expressing Mutant Human Presenilin-1

Barrow, Paul; Empson, Ruth M.; Gladwell, Simon J.; Anderson, Caroline M.; Killick, Richard; Yu, Xin; Jefferys, John G. R.; Duff, Karen

doi:10.1006/nbdi.1999.0276

Cited by 71 publications

(36 citation statements)

References 24 publications

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“…Indeed, families have recently been identified in which PS1 mutations cause frontotemporal dementia [48] (Zekanowski et al, 2006) or cardiomyopathy and heart failure (Li et al, 2006), disorders that lack amyloid pathology. The mechanisms identified in the present study may explain the increased Ca 2+ responses and increased afterhyperpolarization of hippocampal neurons (Barrow et al, 2000) and the defective associative learning (Wang et al, 2004a) previously documented in studies of presenilin mutant mice.…”

Section: Discussionsupporting

confidence: 58%

Presenilin-1 mutation impairs cholinergic modulation of synaptic plasticity and suppresses NMDA currents in hippocampus slices

Wang

Greig

et al. 2009

Neurobiology of Aging

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Presenilin-1 (PS1) mutations cause many cases of early-onset inherited Alzheimer's disease, in part, by increasing the production of neurotoxic forms of amyloid β-peptide (A β). However, Aβ -independent effects of mutant PS1 on neuronal Ca 2+ homeostasis and sensitivity to excitatory neurotransmitters have been reported. Here we show that cholinergic modulation of hippocampal synaptic plasticity is impaired in PS1 mutant knockin (PS1KI) mice. Whereas activation of muscarinic receptors enhances LTP at CA1 synapses of normal mice, it impairs LTP in PS1KI mice. Similarly, mutant PS1 impairs the ability of the cholinesterase inhibitor phenserine to enhance LTP. The NMDA current is decreased in CA1 neurons of PS1KI mice and is restored by intracellular Ca 2+ chelation. Similar alterations in acetylcholine and NMDA receptor-mediated components of synaptic plasticity are evident in 3×TgAD mice with PS1, amyloid precursor protein and tau mutations, suggesting that the adverse effects of mutant PS1 on synaptic plasticity can occur in the absence or presence of amyloid and tau pathologies.

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Section: Discussionsupporting

confidence: 58%

Presenilin-1 mutation impairs cholinergic modulation of synaptic plasticity and suppresses NMDA currents in hippocampus slices

Wang

Greig

et al. 2009

Neurobiology of Aging

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“…On this basis, one may speculate that PS1 mutations could also alter the function of calcium channels, including store-operated calcium channels, since there is a close interaction of the ER and these channels. Findings from Barrow et al (2000), which demonstrated an abnormal, late, and very slow increase in calcium evoked by depolarization in hippocampal neurons from mutant PS1 M146L transgenic mice, are further compatible with this view.…”

Section: Figmentioning

confidence: 53%

Alzheimer's Disease-like Alterations in Peripheral Cells from Presenilin-1 Transgenic Mice

Eckert

Schindowski

Leutner

et al. 2001

Neurobiology of Disease

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Many cases of early-onset inherited Alzheimer's disease (AD) are caused by mutations in the presenilin-1 (PS1) gene. Expression of PS1 mutations in cell culture systems and in primary neurons from transgenic mice increases their vulnerability to cell death. Interestingly, enhanced vulnerability to cell death has also been demonstrated for peripheral lymphocytes from AD patients. We now report that lymphocytes from PS1 mutant transgenic mice show a similar hypersensitivity to cell death as do peripheral cells from AD patients and several cell culture systems expressing PS1 mutations. The cell death-enhancing action of mutant PS1 was associated with increased production of reactive oxygen species and altered calcium regulation, but not with changes of mitochondrial cytochrome c. Our study further emphasizes the pathogenic role of mutant PS1 and may provide the fundamental basis for new efforts to close the gap between studies using neuronal cell lines transfected with mutant PS1, neurons from transgenic animals, and peripheral cells from AD patients.

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“…Indeed we and others have shown enhanced LTP and increased medium and late afterhyperpolarizations (which are mediated by calcium sensitive potassium channels) in mutant PS1 mice [34,[36][37][38]. The underlying molecular mechanisms accounting for these findings are still not fully understood and may be due to an enhancement of the total amount of stored calcium within the ER or it may also be due to alterations in the release kinetics of stored calcium.…”

Section: Calcium Homeostasis and Knowledge Gained From In Vivo Studiesmentioning

confidence: 82%

Calcium dysregulation in Alzheimer's disease: Recent advances gained from genetically modified animals

2005

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Alzheimer's disease is a progressive and irreversible neurodegenerative disorder that leads to cognitive, memory and behavioural impairments. Two decades of research have implicated disturbances of intracellular calcium homeostasis as playing a proximal pathological role in the neurodegeneration associated with Alzheimer's disease. A large preponderance of evidence has been gained from the use of a diverse range of cell lines. Whilst useful in understanding the principal mechanism of neurotoxicity associated with Alzheimer's disease, technical differences, such as cell type or even the form of amyloid-beta used often underlie conflicting results. In this review, we discuss recent contributions that transgenic technology has brought to this field. For example, the triple transgenic mouse model of Alzheimer's disease has implicated intraneuronal accumulation of the amyloid-beta peptide as an initiating factor in synaptic dysfunction and behavioural deficits. Importantly, this synaptic dysfunction occurs prior to cell loss or extracellular amyloid plaque accumulation. The cause of synaptic dysfunction is unknown but it is likely that amyloid-beta and its ability to disrupt intracellular calcium homeostasis plays a key role in this process.

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Functional Phenotype in Transgenic Mice Expressing Mutant Human Presenilin-1

Cited by 71 publications

References 24 publications

Presenilin-1 mutation impairs cholinergic modulation of synaptic plasticity and suppresses NMDA currents in hippocampus slices

Presenilin-1 mutation impairs cholinergic modulation of synaptic plasticity and suppresses NMDA currents in hippocampus slices

Alzheimer's Disease-like Alterations in Peripheral Cells from Presenilin-1 Transgenic Mice

Calcium dysregulation in Alzheimer's disease: Recent advances gained from genetically modified animals

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