A quantitative autoradiographic study of [3H]cAMP binding to cytosolic and particulate protein kinase A in post-mortem brain staged for Alzheimer's disease neurofibrillary changes and amyloid deposits

Bonkale, Willy L.; Cowburn, Richard F.; Ohm, Thomas G.; Bogdanović, Nenad; Fastbom, Johan

doi:10.1016/s0006-8993(98)01307-9

Cited by 47 publications

(30 citation statements)

References 58 publications

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“…The importance of the compartment-specific effects noted herein in response to social isolation are underscored by the fact that patients with neuropsychiatric and neurodegenerative diseases may have cyclic nucleotide deficits in one subcellular compartment but not another (Rahman et al, 1997; Bonkale et al, 1999; Fields et al, 1999; Chang et al, 2003). It is possible to stimulate PDE11A4 catalytic activity via its GAF-A domain (Jager et al, 2012).…”

Section: Discussionmentioning

confidence: 96%

PDE11A regulates social behaviors and is a key mechanism by which social experience sculpts the brain

et al. 2016

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Despite the fact that appropriate social behaviors are vital to thriving in one’s environment, little is understood of the molecular mechanisms controlling social behaviors or how social experience sculpts these signaling pathways. Here, we determine if Phosphodiesterase 11A (PDE11A), an enzyme that is restricted to the ventral hippocampal formation (VHIPP) and that breaks down cAMP and cGMP, regulates social behaviors. PDE11 wild-type (WT), heterozygous (HT), and knockout (KO) mice were tested in various social approach assays and gene expression differences were measured by RNA sequencing. The effect of social isolation on PDE11A4 compartmentalization and subsequent social interactions and social memory was also assessed. Deletion of PDE11A triggered age- and sex-dependent deficits in social approach in specific social contexts but not others. Mice appear to detect altered social behaviors of PDE11A KO mice, because C57BL/6J mice prefer to spend time with a sex-matched PDE11A WT vs. its KO littermate; whereas, a PDE11A KO prefers to spend time with a novel PDE11A KO vs. its WT littermate. Not only is PDE11A required for intact social interactions, we found that 1 month of social isolation vs. group housing decreased PDE11A4 protein expression specifically within the membrane fraction of VHIPP. This isolation-induced decrease in PDE11A4 expression appears functional because social isolation impairs subsequent social approach behavior and social memory in a PDE11A genotype-dependent manner. Pathway analyses following RNA sequencing suggests PDE11A is a key regulator of the oxytocin pathway and membrane signaling, consistent with its pivotal role in regulating social behavior.

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Section: Discussionmentioning

confidence: 96%

PDE11A regulates social behaviors and is a key mechanism by which social experience sculpts the brain

et al. 2016

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“…Synaptic plasticity is a crucial characteristic of neurons that is thought to underlie memory and learning [33–35]. One important regulator of synaptic plasticity is the signalling of cyclic nucleotides [36, 37], which is in turn impaired in the CNS of AD patients [38–42]. CREB, the common downstream target of both cAMP and cGMP signalling and regulator of structural correlates of cognition, is also affected in AD brains [6, 43, 44].…”

Section: Discussionmentioning

confidence: 99%

Reduced cGMP levels in CSF of AD patients correlate with severity of dementia and current depression

et al. 2017

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BackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder, primarily affecting memory. That disorder is thought to be a consequence of neuronal network disturbances and synapse loss. Decline in cognitive function is associated with a high burden of neuropsychiatric symptoms (NPSs) such as depression. The cyclic nucleotides cyclic adenosine-3',5'-monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) are essential second messengers that play a crucial role in memory processing as well as synaptic plasticity and are potential therapeutic targets. Biomarkers that are able to monitor potential treatment effects and that reflect the underlying pathology are of crucial interest.MethodsIn this study, we measured cGMP and cAMP in cerebrospinal fluid (CSF) in a cohort of 133 subjects including 68 AD patients and 65 control subjects. To address the association with disease progression we correlated cognitive status with cyclic nucleotide levels. Because a high burden of NPSs is associated with decrease in cognitive function, we performed an exhaustive evaluation of AD-relevant marker combinations in a depressive subgroup.ResultsWe show that cGMP, but not cAMP, levels in the CSF of AD patients are significantly reduced compared with the control group. Reduced cGMP levels in AD patients correlate with memory impairment based on Mini-Mental State Examination score (r = 0.17, p = 0.048) and tau as a marker of neurodegeneration (r = –0.28, p = 0.001). Moreover, we were able to show that AD patients suffering from current depression show reduced cGMP levels (p = 0.07) and exhibit a higher degree of cognitive impairment than non-depressed AD patients.ConclusionThese results provide further evidence for an involvement of cGMP in AD pathogenesis and accompanying co-morbidities, and may contribute to elucidating synaptic plasticity alterations during disease progression.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-017-0245-y) contains supplementary material, which is available to authorized users.

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“…With the same set of tissues we have previously shown that inositol-1,4,5-triphosphate (IP 3 ) receptors and protein kinase C (PKC) levels decline markedly with progression of neurofibrillary pathology; in entorhinal cortex, subiculum, and CA1 (IP 3 receptors) and entorhinal cortex and all subfields of the hippocampus (PKC; Kurumatani et al, 1998). We have also observed more circumscribed and selective changes in the levels of protein kinase A (PKA; Bonkale et al, 1999) and AC (Garcia-Jiménez et al, 1999). In the present study, we report a decline in the stimulatory effect of GTP on [ 35 S]GTP␥S binding in the entorhinal cortex and CA1 hippocampal subfield that correlates with staging for neurofibrillary changes.…”

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confidence: 81%

Loss of stimulatory effect of guanosine triphosphate on [³⁵S]GTPγS binding correlates with Alzheimer's disease neurofibrillary pathology in entorhinal cortex and CA1 hippocampal subfield

García-Jiménez

Cowburn

Ohm

et al. 2001

J of Neuroscience Research

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Heterotrimeric guanosine triphosphate (GTP)-binding proteins (G-proteins) couple many different cell surface receptor types to intracellular effector mechanisms. Uncoupling between receptors and G-proteins and between G-proteins and adenylyl cyclase (AC) and phospholipase C (PLC) has been described for Alzheimer's disease (AD) brain. However, there is little information on whether altered G-protein signaling in AD is just an end-stage phenomenon or is important for the progression of disease pathology. Here we used [(35)S]GTPgammaS autoradiography to study G-protein distribution in sections of entorhinal cortex and hippocampus from 23 cases staged for neurofibrillary changes and amyloid deposits according to Braak and Braak (Acta Neuropathol. [1991] 82:239-259). We also studied the effects of GTP, which has been found to increase [(35)S]GTPgammaS binding in an Mg(2+)-dependent manner. Results show that the ability of GTP (3 microM) to stimulate [(35)S]GTPgammaS binding declined significantly with staging for neurofibrillary changes in the entorhinal cortex (P < 0.05, ANOVA) and CA1 subfield of the hippocampus (P < 0.05, ANOVA). No significant changes were seen for [(35)S]GTPgammaS binding in the absence of GTP. Our results suggest a decrease in G-protein GTP hydrolysis, which correlates with the progression of AD neurofibrillary changes, in the regions most affected by this pathology. These alterations appear to occur prior to stages corresponding to clinical disease and could lead to an impaired regulation of several signaling systems in AD brain.

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A quantitative autoradiographic study of [3H]cAMP binding to cytosolic and particulate protein kinase A in post-mortem brain staged for Alzheimer's disease neurofibrillary changes and amyloid deposits

Cited by 47 publications

References 58 publications

PDE11A regulates social behaviors and is a key mechanism by which social experience sculpts the brain

PDE11A regulates social behaviors and is a key mechanism by which social experience sculpts the brain

Reduced cGMP levels in CSF of AD patients correlate with severity of dementia and current depression

Loss of stimulatory effect of guanosine triphosphate on [³⁵S]GTPγS binding correlates with Alzheimer's disease neurofibrillary pathology in entorhinal cortex and CA1 hippocampal subfield

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A quantitative autoradiographic study of [3H]cAMP binding to cytosolic and particulate protein kinase A in post-mortem brain staged for Alzheimer's disease neurofibrillary changes and amyloid deposits

Cited by 47 publications

References 58 publications

PDE11A regulates social behaviors and is a key mechanism by which social experience sculpts the brain

PDE11A regulates social behaviors and is a key mechanism by which social experience sculpts the brain

Reduced cGMP levels in CSF of AD patients correlate with severity of dementia and current depression

Loss of stimulatory effect of guanosine triphosphate on [35S]GTPγS binding correlates with Alzheimer's disease neurofibrillary pathology in entorhinal cortex and CA1 hippocampal subfield

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Loss of stimulatory effect of guanosine triphosphate on [³⁵S]GTPγS binding correlates with Alzheimer's disease neurofibrillary pathology in entorhinal cortex and CA1 hippocampal subfield