Loss of inositol 1,4,5-trisphosphate receptor sites and decreased PKC levels correlate with staging of Alzheimer's disease neurofibrillary pathology

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

doi:10.1016/s0006-8993(98)00347-3

Cited by 55 publications

(31 citation statements)

References 42 publications

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“…Previously, we reported a global decrease in PKC levels and a more circumscribed but marked decline in IP 3 levels (Kurumatani et al, 1998). In the same tissue we have also shown a limited decrease in PKA and in specific AC isoforms (Garcia-Jiménez et al, 1999), whereas levels of ryanodine receptor calcium release channels were transiently increased in early stages (Kelliher et al, 1999).…”

Section: Discussionsupporting

confidence: 70%

“…For this, we used post-mortem tissue from the hippocampus and entorhinal cortex of 23 brains that had been staged for AD pathology according to the number and distribution of neurofibrillary changes and amyloid deposits (Braak and Braak, 1991). 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).…”

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confidence: 99%

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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

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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Section: Discussionsupporting

confidence: 70%

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confidence: 99%

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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“…In contrast, the same treatment did not affect the expression of InsP 3 R1 protein in the entorhinal cortex astrocytes, indicating a regional heterogeneity of astrocytes [125]. In human post-mortem tissues, however, an overall decrease in the expression of InsP 3 receptors is observed [133][134][135], which may, however, indicate the overall cell loss and, hence, a decrease in the total expression of receptors. Finally, a chronic treatment with β-amyloid was also reported to increase the store-operated Ca 2+ entry in astrocytes [136,137].…”

Section: Effects Of β-Amyloidmentioning

confidence: 87%

Astroglial calcium signalling in Alzheimer's disease

Verkhratsky

Rodriguez-Arellano

Parpura

et al. 2017

Biochemical and Biophysical Research Communications

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Neuroglial contribution to Alzheimer's disease (AD) is pathologically relevant and highly heterogeneous. Reactive astrogliosis and activation of microglia contribute to neuroinflammation, whereas astroglial and oligodendroglial atrophy affect synaptic transmission and underlie the overall disruption of the central nervous system (CNS) connectome. Astroglial function is tightly integrated with the intracellular ionic signalling mediated by complex dynamics of cytosolic concentrations of free Ca 2+ and Na + . Astroglial ionic signalling is mediated by plasmalemmal ion channels, mainly associated with ionotropic receptors, pumps and solute carrier transporters, and by intracellular organelles comprised of the endoplasmic reticulum and mitochondria. The relative contribution of these molecular cascades/organelles can be plastically remodelled in development and under environmental stress. In AD astroglial Ca 2+ signalling undergoes substantial reorganisation due to an abnormal regulation of expression of Ca 2+ handling molecular cascades.

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“…1 ). PKC and ␣ -secretase are decreased while GSK-3 ␤ and BACE-1 are elevated in AD brains [21][22][23] . AF267B emerges of special therapeutic value since it mimics a physiological effect of ACh that translates into M1 mAChR-mediated beneficial effects on these enzymes, without expected challenges from direct activators of PKC or ␣ -secretase, and/or GSK-3 ␤ or BACE-1 inhibitors, respectively.…”

Section: Discussionmentioning

confidence: 99%

M1 Muscarinic Agonists Target Major Hallmarks of Alzheimer’s Disease – The Pivotal Role of Brain M1 Receptors

Fisher¹

2008

Neurodegener Dis

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The M1 muscarinic receptor (M1 mAChR) is a therapeutic target in Alzheimer’s disease (AD) and the M1-selective muscarinic agonists AF102B, AF150(S) and AF267B are cognitive enhancers and potential disease modifiers. Notably, AF267B decreased cerebrospinal fluid β-amyloid (Aβ₄₀ and Aβ₄₂) in rabbits, decreased brain Aβ levels in hypercholesterolemic rabbits and vascular Aβ₄₂ deposition from the cortex in cholinotoxin-treated rabbits. In triple transgenic AD mice, AF267B reduced cognitive deficits and decreased Aβ₄₂ and tau pathologies in the cortex and hippocampus (not amygdala), via M1 mAChR activation of protein kinase C and a disintegrin and metalloproteinase domain 17 (ADAM17 or TACE) and decreased β-site amyloid precursor protein-cleaving enzyme 1 and glycogen synthase kinase 3β, respectively. AF267B is the first reported low-molecular-weight therapy that targets the major AD hallmarks.

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Loss of inositol 1,4,5-trisphosphate receptor sites and decreased PKC levels correlate with staging of Alzheimer's disease neurofibrillary pathology

Cited by 55 publications

References 42 publications

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

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

Astroglial calcium signalling in Alzheimer's disease

M1 Muscarinic Agonists Target Major Hallmarks of Alzheimer’s Disease – The Pivotal Role of Brain M1 Receptors

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Loss of inositol 1,4,5-trisphosphate receptor sites and decreased PKC levels correlate with staging of Alzheimer's disease neurofibrillary pathology

Cited by 55 publications

References 42 publications

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

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

Astroglial calcium signalling in Alzheimer's disease

M1 Muscarinic Agonists Target Major Hallmarks of Alzheimer’s Disease – The Pivotal Role of Brain M1 Receptors

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Product

Resources

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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

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