Amyloid-β Peptide Inhibits Activation of the Nitric Oxide/cGMP/cAMP-Responsive Element-Binding Protein Pathway during Hippocampal Synaptic Plasticity

Puzzo, Daniela; Vitolo, Ottavio V.; Trinchese, Fabrizio; Jacob, Joel P.; Palmeri, Agostino; Arancio, Ottavio

doi:10.1523/jneurosci.5291-04.2005

Cited by 226 publications

(237 citation statements)

References 64 publications

(111 reference statements)

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“…Low levels of NO (Ͻ100 nM) promote progrowth and antiapoptotic pathways (33). For example, activation of guanyl cyclase by NO and the subsequent phosphorylation of cGMP-dependent protein kinases such as Ras-Raf-extracellular regulated kinase and phosphatidylinositol 3-kinase-Akt (33, 34) play a critical role in neuronal survival (35,36). Neuronal survival is also mediated by NO's inhibition of executioner caspase-3 and caspase-6 (37) where NO can block the conversion of the proenzymes via Akt-mediated phosphorylation or chemically modify and decrease enzyme activity (38,39).…”

Section: Discussionmentioning

confidence: 99%

NO synthase 2 ( NOS2 ) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease

Colton¹,

Vitek²,

Wink

et al. 2006

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

123

103

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Section: Discussionmentioning

confidence: 99%

NO synthase 2 ( NOS2 ) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease

Colton¹,

Vitek²,

Wink

et al. 2006

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

123

103

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“…The phosphorylation of tau at other sites all increased significantly, but not of tau Ser214, suggesting downregulation of PKA activity. Several studies suggest impaired signaling of PKA‐CREB in AD brain (Yamamoto‐Sasaki et al ., 1999; Puzzo et al ., 2005; Liu et al ., 2006). CREB is rapidly dephosphorylated during the postmortem interval (Wang et al ., 2015), but we could not obtain reliable results on the level of CREB phosphorylation in AD brain.…”

Section: Discussionmentioning

confidence: 99%

“…Disturbance of CREB function has been shown to cause memory deficits in many animal models. The downregulation of PKA‐CREB signaling is believed to be responsible for the deficit of learning and memory in AD brain and in some mouse models of AD (Yamamoto‐Sasaki et al ., 1999; Puzzo et al ., 2005; Matsuzaki et al ., 2006; Liang et al ., 2007). …”

Section: Introductionmentioning

confidence: 99%

O‐GlcNAcylation of protein kinase A catalytic subunits enhances its activity: a mechanism linked to learning and memory deficits in Alzheimer's disease

Xie

Jin

et al. 2016

Aging Cell

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SummaryAlzheimer's disease (AD) is characterized clinically by memory loss and cognitive decline. Protein kinase A (PKA)‐CREB signaling plays a critical role in learning and memory. It is known that glucose uptake and O‐GlcNAcylation are reduced in AD brain. In this study, we found that PKA catalytic subunits (PKAcs) were posttranslationally modified by O‐linked N‐acetylglucosamine (O‐GlcNAc). O‐GlcNAcylation regulated the subcellular location of PKAcα and PKAcβ and enhanced their kinase activity. Upregulation of O‐GlcNAcylation in metabolically active rat brain slices by O‐(2‐acetamido‐2‐deoxy‐d‐glucopyranosylidenamino) N‐phenylcarbamate (PUGNAc), an inhibitor of N‐acetylglucosaminidase, increased the phosphorylation of tau at the PKA site, Ser214, but not at the non‐PKA site, Thr205. In contrast, in rat and mouse brains, downregulation of O‐GlcNAcylation caused decreases in the phosphorylation of CREB at Ser133 and of tau at Ser214, but not at Thr205. Reduction in O‐GlcNAcylation through intracerebroventricular injection of 6‐diazo‐5‐oxo‐l‐norleucine (DON), the inhibitor of glutamine fructose‐6‐phosphate amidotransferase, suppressed PKA‐CREB signaling and impaired learning and memory in mice. These results indicate that in addition to cAMP and phosphorylation, O‐GlcNAcylation is a novel mechanism that regulates PKA‐CREB signaling. Downregulation of O‐GlcNAcylation suppresses PKA‐CREB signaling and consequently causes learning and memory deficits in AD.

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“…Thus, alternative targets may exist. Based on previous studies of the effects of soluble Aβ on synaptic plasticity, possible additional candidate targets might include metabotropic glutamate receptors (Wang et al, 2004) and the nitric oxide pathway (Puzzo et al, 2005;Trabace et al, 2007). Whether the profound decrease in DA in response to very low concentrations of Aβ represents synaptic depression also remains to be uncovered.…”

Section: Discussionmentioning

confidence: 99%

Dopamine release in prefrontal cortex in response to β-amyloid activation of α7∗ nicotinic receptors

Khan

Nichols

2007

Brain Research

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The levels of soluble beta amyloid (Aβ) are correlated with symptom severity in Alzheimer's disease. Soluble Aβ has been shown to disrupt synaptic function and it has been proposed that accumulation of soluble Aβ triggers synapse loss over the course of the disease. Numerous studies indicate that soluble Aβ has multiple targets, one of which appears to be the nicotinic acetylcholine receptor, particularly for Aβ concentrations of pM-nM. Moreover, pM-nM soluble Aβ was found to increase presynaptic Ca 2+ levels, suggesting that it may have an impact on neurotransmitter release. In the present study, soluble Aβ was perfused into mouse prefrontal cortex and the effect on the release of dopamine outflow via microdialysis was assessed. In the presence of tetrodotoxin, Aβ 1-42 at 100nM evoked the release of dopamine to ∼170% of basal levels. The Aβ 1-42 -evoked dopamine release was sensitive to antagonists of α7 nicotinic receptors and was absent in mice harboring a null mutation for the α7 nicotinic subunit, but was intact in mice harboring a null mutation for the β2 nicotinic subunit. The control peptide Aβ 40-1 was without effect. In contrast, Aβ 1-42 at 1-10pM caused a profound but slowly developing decrease in dopamine outflow. These results suggest that Aβ alters dopamine release in mouse prefrontal cortex, perhaps involving distinct targets as it accumulates during Alzheimer's disease and leading to disruption of synaptic signaling.

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Amyloid-β Peptide Inhibits Activation of the Nitric Oxide/cGMP/cAMP-Responsive Element-Binding Protein Pathway during Hippocampal Synaptic Plasticity

Abstract: Amyloid-␤ (A␤),

Cited by 226 publications

References 64 publications

NO synthase 2 ( NOS2 ) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease

NO synthase 2 ( NOS2 ) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease

O‐GlcNAcylation of protein kinase A catalytic subunits enhances its activity: a mechanism linked to learning and memory deficits in Alzheimer's disease

Dopamine release in prefrontal cortex in response to β-amyloid activation of α7∗ nicotinic receptors

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