Modulation of synaptic plasticity and Tau phosphorylation by wild-type and mutant presenilin1

Dewachter, Ilse; Ris, Lauerence; Croes, S.; Borghgraef, Peter; Devijver, Herman; Voets, Thomas; Nilius, Bernd; Godaux, Emile; Leuven, Freddy Van

doi:10.1016/j.neurobiolaging.2006.11.019

Cited by 41 publications

(58 citation statements)

References 59 publications

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“…It was previously reported that neurons lacking PS1 had specific reductions in NMDA receptor-mediated transmission, mea-sured using field potential recordings from hippocampal slices (Dewachter et al, 2008; but see Zhang et al, 2009). To determine whether loss of PS1 reduced NMDA receptor-mediated currents in our cultured neurons, we measured the relative amplitudes of synaptic currents carried by AMPARs and NMDARs by recording in external recording solution lacking magnesium in the absence and presence of the AMPAR antagonist CNQX (10 M).…”

Section: Resultsmentioning

confidence: 99%

“…1 D). It may be that the decrease in NMDAR-mediated transmission seen in adult hippocampal slices derived from PS1 KO mice (Dewachter et al, 2008) reflects a compensatory mechanism that develops over several months, and is not an immediate and direct effect of eliminating PS1.…”

Section: Resultsmentioning

confidence: 99%

“…Only a handful of studies to date have investigated the normal role of WT PS1 in synaptic function by examining the effects of selectively eliminating PS1 (Feng et al, 2001;Yu et al, 2001;Parent et al, 2005;Dewachter et al, 2008;Zhang et al, 2009, their supplemental information). To extend our knowledge about PS1 in normal neuronal function, we performed a detailed analysis of the consequences of losing PS1 on a variety of features of synaptic transmission.…”

Section: Discussionmentioning

confidence: 99%

“…Although conditional PS1 loss in adult cerebral cortex had no effect on evoked field EPSPs recorded in hippocampal slices (Feng et al, 2001;Yu et al, 2001; but see Dewachter et al, 2008), loss of PS1 was reported to increase the frequency of spontaneous neurotransmitter release in cultured cortical neurons derived from PS1 knock-out (KO) mice (Parent et al, 2005). These results suggest that PS1 might play a selective role in action potential-independent release, but the mechanisms responsible for this remain to be identified.…”

Section: Introductionmentioning

confidence: 99%

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A Novel Role for γ-Secretase: Selective Regulation of Spontaneous Neurotransmitter Release from Hippocampal Neurons

Pratt¹,

Zhu²,

Watari³

et al. 2011

J. Neurosci.

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With a multitude of substrates, ␥-secretase is poised to control neuronal function through a variety of signaling pathways. Presenilin 1 (PS1) is an integral component of ␥-secretase and is also a protein closely linked to the etiology of Alzheimer's disease (AD). To better understand the roles of ␥-secretase and PS1 in normal and pathological synaptic transmission, we examined evoked and spontaneous neurotransmitter release in cultured hippocampal neurons derived from PS1 knock-out (KO) mice. We found no changes in the size of evoked synaptic currents, short-term plasticity, or apparent calcium dependence of evoked release. The rate of spontaneous release from PS1 KO neurons was, however, approximately double that observed in wild-type (WT) neurons. This increase in spontaneous neurotransmission depended on calcium influx but did not require activation of voltage-gated calcium channels or presynaptic NMDA receptors or release of calcium from internal stores. The rate of spontaneous release from PS1 KO neurons was significantly reduced by lentivirus-mediated expression of WT PS1 or familial AD-linked M146V PS1, but not the D257A PS1 mutant that does not support ␥-secretase activity. Treatment of WT neuronal cultures with ␥-secretase inhibitor mimicked the loss of PS1, leading to a selective increase in spontaneous release without any change in the size of evoked synaptic currents. Together, these results identify a novel role for ␥-secretase in the control of spontaneous neurotransmission through modulation of low-level tonic calcium influx into presynaptic axon terminals.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A Novel Role for γ-Secretase: Selective Regulation of Spontaneous Neurotransmitter Release from Hippocampal Neurons

Pratt¹,

Zhu²,

Watari³

et al. 2011

J. Neurosci.

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“…22 Brains were removed and stored in Karnovsky's solution. Vibratome sections 300 m thick were incubated with 1% osmium tetroxide before dehydration via a graded series of ethanol and impregnation with Agar100 resin.…”

Section: Ultrastructural Analysismentioning

confidence: 99%

Dendritic Degeneration, Neurovascular Defects, and Inflammation Precede Neuronal Loss in a Mouse Model for Tau-Mediated Neurodegeneration

Jaworski

Lechat

Demedts

et al. 2011

The American Journal of Pathology

105

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Adeno-associated virus (AAV)-mediated expression of wild-type or mutant P301L protein tau produces massive degeneration of pyramidal neurons without protein tau aggregation. We probed this novel model for genetic and structural factors and early parameters of pyramidal neurodegeneration. In yellow fluorescent protein-expressing transgenic mice, intracerebral injection of AAV-tauP301L revealed early damage to apical dendrites of CA1 pyramidal neurons, whereas their somata remained normal. Ultrastructurally, more and enlarged autophagic vacuoles were contained in degenerating dendrites and manifested as dark, discontinuous, vacuolated processes surrounded by activated astrocytes. Dendritic spines were lost in AAV-tauP301L-injected yellow fluorescent protein-expressing transgenic mice, and ultrastructurally, spines appeared dark and degenerating. In CX3CR1 EGFP/EGFP -deficient mice, microglia were recruited early to neurons expressing human tau. The inflammatory response was accompanied by extravasation of plasma immunoglobulins. ␣2-Macroglobulin, but neither albumin nor transferrin, became lodged in the brain parenchyma. Large proteins, but not Evans blue, entered the brain of mice injected with AAV-tauP301L. Ultrastructurally, brain capillaries were constricted and surrounded by swollen astrocytes with extensions that contacted degenerating dendrites and axons. Together, these data corroborate the hypothesis that neuroinflammation participates essentially in tau-mediated neurodegeneration, and the model recapitulates early dendritic defects reminiscent of "dendritic amputation" in Alzheimer's disease.

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Analyzing dendritic spine pathology in Alzheimer’s disease: problems and opportunities

et al. 2015

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Synaptic failure is an immediate cause of cognitive decline and memory dysfunction in Alzheimer’s disease. Dendritic spines are specialized structures on neuronal processes, on which excitatory synaptic contacts take place and the loss of dendritic spines directly correlates with the loss of synaptic function. Dendritic spines are readily accessible for both in vitro and in vivo experiments and have, therefore, been studied in great detail in Alzheimer’s disease mouse models. To date, a large number of different mechanisms have been proposed to cause dendritic spine dysfunction and loss in Alzheimer’s disease. For instance, amyloid beta fibrils, diffusible oligomers or the intracellular accumulation of amyloid beta have been found to alter the function and structure of dendritic spines by distinct mechanisms. Furthermore, tau hyperphosphorylation and microglia activation, which are thought to be consequences of amyloidosis in Alzheimer’s disease, may also contribute to spine loss. Lastly, genetic and therapeutic interventions employed to model the disease and elucidate its pathogenetic mechanisms in experimental animals may cause alterations of dendritic spines on their own. However, to date none of these mechanisms have been translated into successful therapeutic approaches for the human disease. Here, we critically review the most intensely studied mechanisms of spine loss in Alzheimer’s disease as well as the possible pitfalls inherent in the animal models of such a complex neurodegenerative disorder.

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Modulation of synaptic plasticity and Tau phosphorylation by wild-type and mutant presenilin1

Cited by 41 publications

References 59 publications

A Novel Role for γ-Secretase: Selective Regulation of Spontaneous Neurotransmitter Release from Hippocampal Neurons

A Novel Role for γ-Secretase: Selective Regulation of Spontaneous Neurotransmitter Release from Hippocampal Neurons

Dendritic Degeneration, Neurovascular Defects, and Inflammation Precede Neuronal Loss in a Mouse Model for Tau-Mediated Neurodegeneration

Analyzing dendritic spine pathology in Alzheimer’s disease: problems and opportunities

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