Inhibition of PKCδ reduces amyloid-β levels and reverses Alzheimer disease phenotypes

Du, Ying; Zhao, Yingjun; Li, Chuan; Zheng, Qiuyang; Tian, Jing; Li, Zhuyi; Huang, Timothy; Zhang, Wei; Xu, Huaxi

doi:10.1084/jem.20171193

Cited by 54 publications

(45 citation statements)

References 82 publications

(113 reference statements)

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“…One unexpected finding of our study was the transient reduction of APP despite persistent PCKβ knockdown. Past studies of PKC modulators in APP transgenic mice have generally tested just a single time point of shorter duration than examined here, and none have suggested a mechanism based on APP stability (49,50,(53)(54)(55)(56). We found that transgenic APP levels were significantly reduced following 1 month of PKCβ knockdown, but this effect lost potency as the animals aged.…”

Section: Discussionmentioning

confidence: 54%

“…Whereas trans-genic overexpression of PKCε diminished Aβ via degradation, PKCδ knockdown in mice lowered Aβ via BACE1. Reduction of PKCδ in primary neurons from APP transgenic mice decreased BACE1 expression, β-site APP cleavage and Aβ production, while chronic treatment with rotterlin to inhibit PKCδ in vivo reiterated these effects and delayed plaque onset (50). These two experiments hint that PKC isoforms may act in opposition to control Aβ levels, yet few isoforms have been selectively manipulated in vivo to isolate their effect.…”

Section: Discussionmentioning

confidence: 97%

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Cross-species genetic screens to identify kinase targets for APP reduction in Alzheimer's disease

Huichalaf¹,

Al‐Ramahi

Park³

et al. 2019

Human Molecular Genetics

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An early hallmark of Alzheimer's disease is the accumulation of amyloid-β (Aβ), inspiring numerous therapeutic strategies targeting this peptide. An alternative approach is to destabilize the amyloid beta precursor protein (APP) from which Aβ is derived. We interrogated innate pathways governing APP stability using a siRNA screen for modifiers whose own reduction diminished APP in human cell lines and transgenic Drosophila. As proof of principle, we validated PKCβ-a known modifier identified by the screen-in an APP transgenic mouse model. PKCβ was genetically targeted using a novel adeno-associated virus shuttle vector to deliver microRNA-adapted shRNA via intracranial injection. In vivo reduction of PKCβ initially diminished APP and delayed plaque formation. Despite persistent PKCβ suppression, the effect on APP and amyloid diminished over time. Our study advances this approach for mining druggable modifiers of disease-associated proteins, while cautioning that prolonged in vivo validation may be needed to reveal emergent limitations on efficacy.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 97%

Cross-species genetic screens to identify kinase targets for APP reduction in Alzheimer's disease

Huichalaf¹,

Al‐Ramahi

Park³

et al. 2019

Human Molecular Genetics

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“…Several studies uncovered crucial functions of PRKCD in AD: a) A stimulated protein kinase C delta type (PRKCD) to phosphorylate myristoylated alanine-rich C-kinase substrate (MARCKS) in microglia 19 and phosphorylation of MARCKS was observed in microglia within plaques 20 ; and b) inhibition of PRKCD reverse A levels 21 . Spleen tyrosine kinase (SYK) has been shown to play a role in AD pathological lesions, and SYK was therefore considered as a potential drug target for AD 22 .…”

Section: Discovery Of Disease-associated Microglia Specific Molecularmentioning

confidence: 99%

Multimodal single-cell/nucleus RNA-sequencing data analysis uncovers molecular networks between disease-associated microglia and astrocytes with implications for drug repurposing in Alzheimer’s disease

Zhang

Huang

et al. 2020

Preprint

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Systematic identification of molecular networks in disease relevant immune cells of the nervous system is critical for elucidating the underlying pathophysiology of Alzheimer's disease (AD). Two key immune cell types, disease-associated microglia (DAM) and disease-associated astrocytes (DAA), are biologically involved in AD pathobiology. Therefore, uncovering molecular determinants of DAM and DAA will enhance our understanding of AD biology, potentially identifying novel therapeutic targets for AD treatment. Here, we present an integrative, network-based methodology to uncover conserved molecular networks between DAM and DAA. Specifically, we leverage single-cell and single-nucleus RNA sequencing data from both AD transgenic mouse models and AD patient brains, drug-target networks, metabolite-enzyme associations, and the human protein-protein interactome, along with large-scale patient data validation from the MarketScan Medicare Supplemental Database. We find that common and unique molecular network regulators between DAM (i.e, PAK1, MAPK14, and SYK) and DAA (i.e., NFKB1, FOS, and JUN) are significantly enriched by multiple neuro-inflammatory pathways and well-known genetic variants (i.e., BIN1) from genome-wide association studies. Further network analysis reveal shared immune pathways between DAM and DAA, including Fc gamma R-mediated phagocytosis, Th17 cell differentiation, and chemokine signaling. Furthermore, integrative metabolite-enzyme network analyses imply that fatty acids (i.e., elaidic acid) and amino acids (i.e., glutamate, serine, and phenylalanine) may trigger molecular alterations between DAM and DAA. Finally, we prioritize repurposed drug candidates for potential treatment of AD by agents that specifically reverse dysregulated gene expression of DAM or DAA, including an antithrombotic anticoagulant triflusal, a beta2-adrenergic receptor agonist salbutamol, and the steroid medications (fluticasone and mometasone). Individuals taking fluticasone (an approved anti-inflammatory and inhaled corticosteroid) displayed a significantly decreased incidence of AD (hazard ratio (HR) = 0.858, 95% confidence interval [CI] 0.829-0.888, P < 0.0001) in retrospective case-control validation. Furthermore, propensity score matching cohort studies also confirmed an association of mometasone with reduced incidence of AD in comparison to fluticasone (HR =0.921, 95% CI 0.862-0.984, P < 0.0001).

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“…Since PKCs-related pathways have been involved in the control of memory and learning processes, their role in cognitive disorders were investigated [43,44,45,46]. These cognitive disorders include Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Vascular Dementia, and Huntington Disease (HD).…”

Section: Protein Kinase Cs In Brain and Neurological Diseasesmentioning

confidence: 99%

Age-Dependent Levels of Protein Kinase Cs in Brain: Reduction of Endogenous Mechanisms of Neuroprotection

Pastore

Pacifici

Dave

et al. 2019

IJMS

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Neurodegenerative diseases are among the leading causes of mortality and disability worldwide. However, current therapeutic approaches have failed to reach significant results in their prevention and cure. Protein Kinase Cs (PKCs) are kinases involved in the pathophysiology of neurodegenerative diseases, such as Alzheimer’s Disease (AD) and cerebral ischemia. Specifically ε, δ, and γPKC are associated with the endogenous mechanism of protection referred to as ischemic preconditioning (IPC). Existing modulators of PKCs, in particular of εPKC, such as ψεReceptor for Activated C-Kinase (ψεRACK) and Resveratrol, have been proposed as a potential therapeutic strategy for cerebrovascular and cognitive diseases. PKCs change in expression during aging, which likely suggests their association with IPC-induced reduction against ischemia and increase of neuronal loss occurring in senescent brain. This review describes the link between PKCs and cerebrovascular and cognitive disorders, and proposes PKCs modulators as innovative candidates for their treatment. We report original data showing εPKC reduction in levels and activity in the hippocampus of old compared to young rats and a reduction in the levels of δPKC and γPKC in old hippocampus, without a change in their activity. These data, integrated with other findings discussed in this review, demonstrate that PKCs modulators may have potential to restore age-related reduction of endogenous mechanisms of protection against neurodegeneration.

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Inhibition of PKCδ reduces amyloid-β levels and reverses Alzheimer disease phenotypes

Abstract: Du et al. demonstrate that PKCδ modulates BACE1 expression and amyloidogenic amyloid precursor protein processing. Inhibition of PKCδ markedly reduces BACE1 expression, β-amyloid levels, and amyloid plaque formation and also rescues cognitive deficits in Alzheimer disease mouse models.

Cited by 54 publications

References 82 publications

Cross-species genetic screens to identify kinase targets for APP reduction in Alzheimer's disease

Cross-species genetic screens to identify kinase targets for APP reduction in Alzheimer's disease

Multimodal single-cell/nucleus RNA-sequencing data analysis uncovers molecular networks between disease-associated microglia and astrocytes with implications for drug repurposing in Alzheimer’s disease

Age-Dependent Levels of Protein Kinase Cs in Brain: Reduction of Endogenous Mechanisms of Neuroprotection

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