Overexpression of protein kinase Mζ in the hippocampus mitigates Alzheimer’s disease-related cognitive deficit in rats

Amini, Niloufar; Azad, Reza Roosta; Motamedi, Fereshteh; Mirzapourdelavar, Hadi; Ghasemi, Soheil; Aliakbari, Shayan; Pourbadie, Hamid Gholami

doi:10.1016/j.brainresbull.2020.11.001

Cited by 6 publications

(3 citation statements)

References 52 publications

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“…CT-KIBRA may also modify synapse strength through binding to other PKC isoforms implicated in synaptic plasticity regulation, such as PKCγ, α, β, and ι, which were reduced in postsynaptic fractions prepared from KIBRA knockout mice (66). While our study highlights the critical role for KIBRA in modulating synapse repair to recover memory, and showed that PKMζ overexpression alone is not sufficient to restore plasticity in neurons with pathogenic tau, a recent study found that the memory impairments caused by oligomeric amyloid β toxicity in rats were alleviated by PKMζ overexpression in hippocampus (68). Thus, enhanced PKMζ levels may be sufficient to promote synapse function under certain pathogenic conditions but not others.…”

Section: Discussioncontrasting

confidence: 56%

KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss

Kauwe

Pareja-Navarro

Yao

et al. 2023

Preprint

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Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer's disease (AD) and related tauopathies. Here, we define a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIdney/BRAin (KIBRA) protein (CT-KIBRA). We show that CT-KIBRA restores plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we find that CT-KIBRA binds to and stabilizes protein kinase Mζ (PKMζ) to maintain synaptic plasticity and memory despite tau-mediated pathogenesis. In humans we find that reduced KIBRA in brain and increased KIBRA in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. Thus, our results distinguish KIBRA both as a novel biomarker of synapse dysfunction in AD and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.

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Section: Discussioncontrasting

confidence: 56%

KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss

Kauwe

Pareja-Navarro

Yao

et al. 2023

Preprint

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“…Rat hippocampal neurons were washed in ECS then incubated with 300 μM Glycine (Sigma-Aldrich) in ECS for 5 minutes fractions prepared from KIBRA-KO mice (69). While our study highlighted the critical role for KIBRA in modulating synapse repair to recover memory and showed that PKMζ overexpression alone was not sufficient to restore plasticity in neurons with pathogenic tau, a recent study found that the memory impairments caused by oligomeric amyloid β toxicity in rats were alleviated by PKMζ overexpression in the hippocampus (71). Thus, enhanced PKMζ levels may be sufficient to promote synapse function under certain pathogenic conditions but not others.…”

Section: Micementioning

confidence: 66%

KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss

Kauwe,

Pareja-Navarro,

Yao

et al. 2024

Journal of Clinical Investigation

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“…Although aPKCs are better known for their function in regulating cell polarity during embryonic development, previous studies also revealed their potential role during adulthood. The N-terminal truncated PKCζ was found to be necessary for maintaining synaptic potentiation in hippocampal slices ( 17 , 18 ). Another previous study found that the intraventricular injection of PKCζ can activate synapses, but inhibiting aPKCs could suppress late-stage long-term potentiation (LTP) in vivo ( 19 ).…”

Section: Introductionmentioning

confidence: 99%

A novel non‑selective atypical PKC agonist could protect neuronal cell line from Aβ‑oligomer induced toxicity by suppressing Aβ generation

Zou

Pan

et al. 2022

Mol Med Rep

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Atypical protein kinase C (aPKCs) serve key functions in embryonic development by regulating apical-basal polarity. Previous studies have shed light on their roles during adulthood, especially in the development of Alzheimer's disease (AD). Although the crystal structure of PKCι has been resolved, an agonist of aPKCs remains to be discovered. In the present study, by using the Discovery Studio program and LibDock methodology, a small molecule library (K66-X4436 KINA Set) of compounds were screened for potential binding to PKCι. Subsequently, the computational docking results were validated using affinity selection-mass spectrometry, before in vitro kinase activity was used to determine the function of the hit compounds. A cell-based model assay that can mimic the pathology of AD was then established and used to assess the function of these hit compounds. As a result, the aPKC agonist Z640 was identified, which could bind to PKCι in silico, in vitro and in this cell-based model. Z640 was further confirmed as a non-selective aPKC agonist that can activate the kinase activity of both PKCι and PKCζ. In the cell-based assay, Z640 was found to protect neuronal cell lines from amyloid-β (Aβ) oligomer-induced cell death by reducing reactive oxygen species production and restore mitochondrial function. In addition, Z640 could reduce Aβ40 generation in a dose-dependent manner and shift amyloid precursor protein processing towards the non-amyloid pathway. To conclude, the present study is the first, to the best of the authors' knowledge to identify an aPKC agonist by combining computer-assisted drug discovery and cell-based assays. The present study also revealed that aPKC agonists have therapeutic potential for the treatment of AD.

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Overexpression of protein kinase Mζ in the hippocampus mitigates Alzheimer’s disease-related cognitive deficit in rats

Cited by 6 publications

References 52 publications

KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss

KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss

KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss

A novel non‑selective atypical PKC agonist could protect neuronal cell line from Aβ‑oligomer induced toxicity by suppressing Aβ generation

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