Insulin deficiency results in reversible protein kinase A activation and tau phosphorylation

Harg, Judith M. van der; Eggels, Leslie; Bangel, Fabian N.; Ruigrok, Silvie R.; Zwart, Rob; Hoozemans, Jeroen J. M.; Fleur, Susanne E. la; Scheper, Wiep

doi:10.1016/j.nbd.2017.04.005

Cited by 28 publications

(18 citation statements)

References 75 publications

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“…While one might expect a decrease in the GSK3β (S9) (considered to inactivate the kinase activity) with an increase in the Ser 216 phosphorylated GSK3β isoform (considered to activate the kinase activity) to accompany the increased tau phosphorylation under 3NP exposure, we detected an increase in the GSK3β (S9) in the 3NP treated mice with each of the protocols (acute and moderate), with the 3NP-DM-Tau-tg-mice showing also a decrease in GSK3β (Y216). This seems to be in accord with the similar regulation taking place under neurotoxic conditions, such as under exposure to amyloid-beta or apoE4 (Cedazo-Mínguez et al, 2003), as well as in experimental diabetes, traumatic brain injury, and cerebral ischemia in rodents (Planel et al, 2007;Zhao et al, 2012;Morales-Corraliza et al, 2016;Kisoh et al, 2017;van der Harg et al, 2017), where at early stages following model induction indeed the expected decrease in GSK3β (S9) [with also an increase in GSK3β (Y216) was detected, but at latter stages the opposite effects were detected]. These time dependent effects may point to an early stage of damage taking place and further followed by attempts for correction.…”

Section: Discussionsupporting

confidence: 80%

“…decreased (and their ratio increased). These changes in the levels of phosphorylated GSK3β forms presented by us here may fit the reports of increased GSK3β (S9) level (time dependent) under neurotoxic conditions, such as amyloid-beta and apoE4 milieu [as well as experimental diabetes, traumatic brain injury and cerebral ischemia, and some changes in GSK3β (Y216) levels (Planel et al, 2007;Zhao et al, 2012;Morales-Corraliza et al, 2016;Kisoh et al, 2017;van der Harg et al, 2017)]. We also noticed that while the 5-month old 3NP-DM-Tautg mice (moderate long-term protocol) showed a decrease in total GSK3β level (Figure 3A), the 13-month old 3NP-DM-Tau-tg mice (acute short-term protocol) (Figure 3B), as well as the 13-month old 3NP-WT-mice (acute short-term protocol) (Figures 4A,B) showed an increase in total GSK3β level (may be related to the different age and 3NP exposure protocols).…”

Section: Alterations In the Levels Of Gsk And Itssupporting

confidence: 89%

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Exposure to 3-Nitropropionic Acid Mitochondrial Toxin Induces Tau Pathology in Tangle-Mouse Model and in Wild Type-Mice

Lahiani-Cohen

Touloumi

Lagoudaki

et al. 2020

Front. Cell Dev. Biol.

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Oxidative stress, particularly of mitochondrial origin, plays an important role in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD) and other tauopathies. Controversies regarding the responses of tau phosphorylation state to various stimuli causing oxidative stress have been reported. Here we investigated the effect of 3-nitropropionic acid (3NP), a mitochondrial toxin which induces oxidative stress, on the tangle-pathology in our previously generated double mutant (E257T/P301S, DM) -Tau-tg mice and in WT-mice. We detected an increase in tangle pathology in the hippocampus and cortex of the DM-Tau-tg mice following exposure of the mice to the toxin, as well as generation of tangles in WT-mice. This increase was accompanied with alterations in the level of the glycogen synthase kinase 3β (GSK3β), the kinase which phosphorylates the tau protein, and in the phosphorylation state of this kinase. A response of microglial cells was noticed. These results point to the involvement of mitochondrial dysfunction in the development of the tangle-pathology and may suggest that interfering with mitochondrial dysfunction may have an anti-tangle therapeutic potential.

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Section: Discussionsupporting

confidence: 80%

Section: Alterations In the Levels Of Gsk And Itssupporting

confidence: 89%

Exposure to 3-Nitropropionic Acid Mitochondrial Toxin Induces Tau Pathology in Tangle-Mouse Model and in Wild Type-Mice

Lahiani-Cohen

Touloumi

Lagoudaki

et al. 2020

Front. Cell Dev. Biol.

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“…On the other hand, a recent study did not observe decreases in PKA levels in the prefrontal cortex of AD patients [95]. In addition, a very recent study showed that insulin deficiency induces the activity of PKA and results in tau phosphorylation [96]. This may suggest that the impairments in the cAMP/CREB pathway might not be solely attributed to PKA activity.…”

Section: Discussionmentioning

confidence: 91%

The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non‐human primate model of Alzheimer's disease

Batista

Forny-Germano

Clarke

et al. 2018

The Journal of Pathology

200

135

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Alzheimer's disease (AD) is a devastating neurological disorder that still lacks an effective treatment, and this has stimulated an intense pursuit of disease‐modifying therapeutics. Given the increasingly recognized link between AD and defective brain insulin signaling, we investigated the actions of liraglutide, a glucagon‐like peptide‐1 (GLP‐1) analog marketed for treatment of type 2 diabetes, in experimental models of AD. Insulin receptor pathology is an important feature of AD brains that impairs the neuroprotective actions of central insulin signaling. Here, we show that liraglutide prevented the loss of brain insulin receptors and synapses, and reversed memory impairment induced by AD‐linked amyloid‐β oligomers (AβOs) in mice. Using hippocampal neuronal cultures, we determined that the mechanism of neuroprotection by liraglutide involves activation of the PKA signaling pathway. Infusion of AβOs into the lateral cerebral ventricle of non‐human primates (NHPs) led to marked loss of insulin receptors and synapses in brain regions related to memory. Systemic treatment of NHPs with liraglutide provided partial protection, decreasing AD‐related insulin receptor, synaptic, and tau pathology in specific brain regions. Synapse damage and elimination are amongst the earliest known pathological changes and the best correlates of memory impairment in AD. The results illuminate mechanisms of neuroprotection by liraglutide, and indicate that GLP‐1 receptor activation may be harnessed to protect brain insulin receptors and synapses in AD. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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“…Increases in cAMP levels and PKA activity have been observed in the cerebral microvessels of AD patients [41], and elevated levels of cAMP in the CSF of AD patients have been reported [42]. Van et al [43] documented an increase p-PKA levels in the temporal cortex of early-stage AD patients. Expression of PKA and p-CREB is decreased in AD patients and in vitro models [44,45], suggesting that PKA and p-CREB levels may vary on different tissues at different stages of disease progression.…”

Section: Discussionmentioning

confidence: 99%

Two Novel Pde11a Genetic Variants Increase Tau Phosphorylations in Early-onset Alzheimer's Disease

Wei

Zhou

Zuo

et al. 2020

Preprint

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Background: Alzheimer’s disease (AD) is a leading cause of dementia in the elderly and has become a major health issue. However, a large number of genetic risk factors remain undiscovered. Methods: To identify novel risk genes and better understand the molecular pathway underlying AD, whole-exome sequencing (WES) was performed in 215 early-onset AD (EOAD) patients and 55 unrelated healthy controls of Han Chinese ethnicity. Subsequent direct sequencing was performed in 620 individuals to validate the selected rare mutations. Computational annotation and in vitro functional studies were performed to evaluate the role of candidate mutations in EOAD and the underlying mechanisms.Results: We identified two rare missense mutations in the phosphodiesterase 11A (PDE11A) gene, resulting in p.Arg202His, and p.Leu756Gln, in 4 individuals with EOAD. Both mutations are located in evolutionarily highly conserved amino acids, are predicted to alter the protein conformation, and classified as pathogenic. Furthermore, we found significantly decreased protein levels of PDE11A in brain samples of AD patients. Expression of PDE11A variants and knockdown experiments with specific short hairpin RNA (shRNA) for PDE11A both resulted in an increase of AD-associated Tau hyperphosphorylation at T181, S404, S202, S416, S214, S396 and AT8 epitopes in vitro. PDE11A variants or PDE11A shRNA also caused increased cAMP levels, protein kinase A (PKA) activation, and cAMP response element-binding protein (CREB) phosphorylation. Additionally, pretreatment with a PKA inhibitor (H89) suppressed PDE11A mutation-induced p-Tau formation.Conclusions: Our results demonstrate that both PDE11A mutations and PDE11A knockdown increase Tau phosphorylation through the cAMP/PKA pathway, suggesting that PDE11A is a novel risk gene for AD. This study provides insight into the involvement of Tau phosphorylation via the cAMP/PKA pathway in EOAD pathogenesis and provides a potential new target for intervention.

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Insulin deficiency results in reversible protein kinase A activation and tau phosphorylation

Cited by 28 publications

References 75 publications

Exposure to 3-Nitropropionic Acid Mitochondrial Toxin Induces Tau Pathology in Tangle-Mouse Model and in Wild Type-Mice

Exposure to 3-Nitropropionic Acid Mitochondrial Toxin Induces Tau Pathology in Tangle-Mouse Model and in Wild Type-Mice

The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non‐human primate model of Alzheimer's disease

Two Novel Pde11a Genetic Variants Increase Tau Phosphorylations in Early-onset Alzheimer's Disease

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