β-Amyloid precursor protein (APP) and APP-RNA are rapidly affected by glutamate in cultured neurons

Willoughby, David A.; Rozovsky, Irina; Lo, Amy Cheuk Yin; Finch, Caleb E.

doi:10.1007/bf02736785

Cited by 17 publications

(7 citation statements)

References 73 publications

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“…Although neither apoptosis nor AMPA exposure altered the pattern of expression of APP mRNA, application of NMDA increased the neuronal transcription of KPI-APP proteins and decreased the amount of mRNA encoding for the normally dominant APP 695 . The modification of APP transcripts described in the present study is in agreement with a previous report indicating that glutamate exposure induced the expression of KPIAPPs in neurons (Willoughby et al, 1995). In addition, we demonstrate that this modification of APP expression is a result of an NMDA-mediated Ca 2ϩ influx and subsequent CaM/CaMK axis activation.…”

Section: Discussionsupporting

confidence: 93%

NMDA Receptor Activation Inhibits α-Secretase and Promotes Neuronal Amyloid-β Production

Lesné¹,

Ali²,

Gabriel³

et al. 2005

J. Neurosci.

178

127

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Acute brain injuries have been identified as a risk factor for developing Alzheimer's disease (AD). Because glutamate plays a pivotal role in these pathologies, we studied the influence of glutamate receptor activation on amyloid-␤ (A␤) production in primary cultures of cortical neurons. We found that sublethal NMDA receptor activation increased the production and secretion of A␤. This effect was preceded by an increased expression of neuronal Kunitz protease inhibitory domain (KPI) containing amyloid-␤ precursor protein (KPI-APP) followed by a shift from ␣-secretase to ␤-secretase-mediated APP processing. This shift is a result of the inhibition of the ␣-secretase candidate tumor necrosis factor-␣ converting enzyme (TACE) when associated with neuronal KPI-APPs. This KPI-APP/ TACE interaction was also present in AD brains. Thus, our findings reveal a cellular mechanism linking NMDA receptor activation to neuronal A␤ secretion. These results suggest that even mild deregulation of the glutamatergic neurotransmission may increase A␤ production and represent a causal risk factor for developing AD.

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Section: Discussionsupporting

confidence: 93%

NMDA Receptor Activation Inhibits α-Secretase and Promotes Neuronal Amyloid-β Production

Lesné¹,

Ali²,

Gabriel³

et al. 2005

J. Neurosci.

178

127

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“…Previous reports indicated a link between the induction of KPI-APP isoforms and glutamate exposure (Willoughby et al, 1995) or NMDA treatment (Lesné et al, 2005) in neurons. However, to our knowledge, no published data are available describing a possible link between extrasynaptic NMDAR activation and amyloidogenesis.…”

mentioning

confidence: 96%

Activation of Extrasynaptic, But Not Synaptic, NMDA Receptors Modifies Amyloid Precursor Protein Expression Pattern and Increases Amyloid-β Production

Bordji¹,

Becerril-Ortega²,

Nicole³

et al. 2010

J. Neurosci.

170

147

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Calcium is a key mediator controlling essential neuronal functions depending on electrical activity. Altered neuronal calcium homeostasis affects metabolism of amyloid precursor protein (APP), leading to increased production of ␤-amyloid (A␤), and contributing to the initiation of Alzheimer's disease (AD). A linkage between excessive glutamate receptor activation and neuronal A␤ release was established, and recent reports suggest that synaptic and extrasynaptic NMDA receptor (NMDAR) activation may have distinct consequences in plasticity, gene regulation, and neuronal death. Here, we report for the first time that prolonged activation of extrasynaptic NMDAR, but not synaptic NMDAR, dramatically increased the neuronal production of A␤. This effect was preceded by a shift from APP695 to Kunitz protease inhibitory domain (KPI) containing APPs (KPI-APPs), isoforms exhibiting an important amyloidogenic potential. Conversely, after synaptic NMDAR activation, we failed to detect any KPI-APP expression and neuronal A␤ production was not modified. Calcium imaging data showed that intracellular calcium concentration after extrasynaptic NMDAR stimulation was lower than after synaptic activation. This suggests distinct signaling pathways for each pool of receptors. We found that modification of neuronal APP expression pattern triggered by extrasynaptic NMDAR activation was regulated at an alternative splicing level involving calcium-/ calmodulin-dependent protein kinase IV, but overall APP expression remained identical. Finally, memantine dose-dependently inhibited extrasynaptic NMDAR-induced KPI-APPs expression as well as neuronal A␤ release. Altogether, these data suggest that a chronic activation of extrasynaptic NMDAR promotes amyloidogenic KPI-APP expression leading to neuronal A␤ release, representing a causal risk factor for developing AD.

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“…Conversely, KPI(-)APP is signifi cantly reduced in AD [30] . Sustained NMDA-receptor activation can regulate alternative splicing of the APP premRNA in neurons [28] and KPI(+)APP RNA, but not KPI(-)APP RNA, is upregulated in response to experimental lesions in which neurotoxicity is dependent on NMDA receptor activation in AD hippocampus [31,32] ; thus Glu treatment rapidly induce KPI(+)APP RNA but not KPI(-)APP RNA. Induction of KPI(+)RNA precede Glu-induced neuronal cell death and is partially blocked by an NMDA-receptor antagonist.…”

Section: Kpi Involvement In Neurodegenerative Diseasesmentioning

confidence: 99%

APP Processing and the APP-KPI Domain Involvement in the Amyloid Cascade

et al. 2005

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Alternative APP mRNA splicing can generate isoforms of APP containing a Kunitz protease inhibitor (KPI) domain. KPI is one of the main serine protease inhibitors. Protein and mRNA KPI(+)APP levels are elevated in Alzheimer’s disease (AD) brain and are associated with increased amyloid beta deposition. In the last years increasing evidence on multiple points in the amyloid cascade where KPI(+)APP is involved has been accumulated, admitting an outstanding position in the pathogenesis of AD to the KPI domain. This review focuses on the APP processing, the molecular activity of KPI and its physiological and pathological roles and the KPI involvement in the amyloid cascade through the nerve growth factor, the lipoprotein receptor-related protein, the tumor necrosis factor-alpha converting enzyme and the Notch1 protein.

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β-Amyloid precursor protein (APP) and APP-RNA are rapidly affected by glutamate in cultured neurons

Cited by 17 publications

References 73 publications

NMDA Receptor Activation Inhibits α-Secretase and Promotes Neuronal Amyloid-β Production

NMDA Receptor Activation Inhibits α-Secretase and Promotes Neuronal Amyloid-β Production

Activation of Extrasynaptic, But Not Synaptic, NMDA Receptors Modifies Amyloid Precursor Protein Expression Pattern and Increases Amyloid-β Production

APP Processing and the APP-KPI Domain Involvement in the Amyloid Cascade

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