The decreased level of casein kinase 2 in brain cortex of schizophrenic and Alzheimer's disease patients

AbstractAlzheimer’s disease (AD) is the most common age-related neurodegenerative disorder. Increased Aβ production plays a fundamental role in the pathogenesis of the disease and BACE1, the protease that triggers the amyloidogenic processing of APP, is a key protein and a pharmacological target in AD. Changes in neuronal activity have been linked to BACE1 expression and Aβ generation, but the underlying mechanisms are still unclear. We provide clear evidence for the role of Casein Kinase 2 in the control of activity-driven BACE1 expression in cultured primary neurons, organotypic brain slices, and murine AD models. More specifically, we demonstrate that neuronal activity promotes Casein Kinase 2 dependent phosphorylation of the translation initiation factor eIF4B and this, in turn, controls BACE1 expression and APP processing. Finally, we show that eIF4B expression and phosphorylation are increased in the brain of APPPS1 and APP-KI mice, as well as in AD patients. Overall, we provide a definition of a mechanism linking brain activity with amyloid production and deposition, opening new perspectives from the therapeutic standpoint.

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Brain levels of cytoplasmic casein kinase 2 and its substrate proteins in Alzheimer's disease

Bulletin of Experimental Biology and Medicine ◽

10.1007/bf00790099 ◽

1992 ◽

Vol 113 (6) ◽

pp. 804-806

Author(s):

M. V. Aksenova ◽

M. V. Karaseva ◽

G. Sh. Burbaeva

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Casein Kinase ◽

Casein Kinase 2 ◽

Brain Levels ◽

Substrate Proteins

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Intermittent Hypoxic Conditioning Rescues Cognition and Mitochondrial Bioenergetic Profile in the Triple Transgenic Mouse Model of Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22010461 ◽

2021 ◽

Vol 22 (1) ◽

pp. 461

Author(s):

Sónia C. Correia ◽

Nuno J. Machado ◽

Marco G. Alves ◽

Pedro F. Oliveira ◽

Paula I. Moreira

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Brain Cortex ◽

Neurodegenerative Disorder ◽

Special Focus ◽

Mitochondrial Bioenergetics ◽

Related Phenotype ◽

Brain Resilience ◽

The Brain

The lack of effective disease-modifying therapeutics to tackle Alzheimer’s disease (AD) is unsettling considering the actual prevalence of this devastating neurodegenerative disorder worldwide. Intermittent hypoxic conditioning (IHC) is a powerful non-pharmacological procedure known to enhance brain resilience. In this context, the aim of the present study was to investigate the potential long-term protective impact of IHC against AD-related phenotype, putting a special focus on cognition and mitochondrial bioenergetics and dynamics. For this purpose, six-month-old male triple transgenic AD mice (3×Tg-AD) were submitted to an IHC protocol for two weeks and the behavioral assessment was performed at 8.5 months of age, while the sacrifice of mice occurred at nine months of age and their brains were removed for the remaining analyses. Interestingly, IHC was able to prevent anxiety-like behavior and memory and learning deficits and significantly reduced brain cortical levels of amyloid-β (Aβ) in 3×Tg-AD mice. Concerning brain energy metabolism, IHC caused a significant increase in brain cortical levels of glucose and a robust improvement of the mitochondrial bioenergetic profile in 3×Tg-AD mice, as mirrored by the significant increase in mitochondrial membrane potential (ΔΨm) and respiratory control ratio (RCR). Notably, the improvement of mitochondrial bioenergetics seems to result from an adaptative coordination of the distinct but intertwined aspects of the mitochondrial quality control axis. Particularly, our results indicate that IHC favors mitochondrial fusion and promotes mitochondrial biogenesis and transport and mitophagy in the brain cortex of 3×Tg-AD mice. Lastly, IHC also induced a marked reduction in synaptosomal-associated protein 25 kDa (SNAP-25) levels and a significant increase in both glutamate and GABA levels in the brain cortex of 3×Tg-AD mice, suggesting a remodeling of the synaptic microenvironment. Overall, these results demonstrate the effectiveness of the IHC paradigm in forestalling the AD-related phenotype in the 3×Tg-AD mouse model, offering new insights to AD therapy and forcing a rethink concerning the potential value of non-pharmacological interventions in clinical practice.

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Dimensional Changes in Lipid Rafts from Human Brain Cortex Associated to Development of Alzheimer’s Disease. Predictions from an Agent-Based Mathematical Model

International Journal of Molecular Sciences ◽

10.3390/ijms222212181 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12181

Author(s):

Guido Santos ◽

Mario Díaz

Keyword(s):

Alzheimer’S Disease ◽

Mathematical Model ◽

Alzheimer's Disease ◽

Human Brain ◽

Lipid Rafts ◽

Brain Cortex ◽

Clinical Symptoms ◽

Senile Plaques ◽

Amyloid Β ◽

Human Brain Cortex

Alzheimer’s disease (AD) is a neurodegenerative disease caused by abnormal functioning of critical physiological processes in nerve cells and aberrant accumulation of protein aggregates in the brain. The initial cause remains elusive—the only unquestionable risk factor for the most frequent variant of the disease is age. Lipid rafts are microdomains present in nerve cell membranes and they are known to play a significant role in the generation of hallmark proteinopathies associated to AD, namely senile plaques, formed by aggregates of amyloid β peptides. Recent studies have demonstrated that human brain cortex lipid rafts are altered during early neuropathological phases of AD as defined by Braak and Braak staging. The lipid composition and physical properties of these domains appear altered even before clinical symptoms are detected. Here, we use a coarse grain molecular dynamics mathematical model to predict the dimensional evolution of these domains using the experimental data reported by our group in human frontal cortex. The model predicts significant size and frequency changes which are detectable at the earliest neuropathological stage (ADI/II) of Alzheimer’s disease. Simulations reveal a lower number and a larger size in lipid rafts from ADV/VI, the most advanced stage of AD. Paralleling these changes, the predictions also indicate that non-rafts domains undergo simultaneous alterations in membrane peroxidability, which support a link between oxidative stress and AD progression. These synergistic changes in lipid rafts dimensions and non-rafts peroxidability are likely to become part of a positive feedback loop linked to an irreversible amyloid burden and neuronal death during the evolution of AD neuropathology.

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Author Correction: Inhibition of casein kinase 1δ/εimproves cognitive-affective behavior and reduces amyloid load in the APP-PS1 mouse model of Alzheimer’s disease

Scientific Reports ◽

10.1038/s41598-019-51830-5 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

S. Sundaram ◽

S. Nagaraj ◽

H. Mahoney ◽

A. Portugues ◽

W. Li ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Casein Kinase ◽

Affective Behavior ◽

Model Of Alzheimer’S Disease ◽

Amyloid Load

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Elevation of casein kinase 1ε associated with TDP‐43 and tau pathologies in Alzheimer's disease

Brain Pathology ◽

10.1111/bpa.12775 ◽

2019 ◽

Vol 30 (2) ◽

pp. 283-297 ◽

Cited By ~ 2

Author(s):

Jianlan Gu ◽

Wen Hu ◽

Xuefeng Tan ◽

Shuting Qu ◽

Dandan Chu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Casein Kinase

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Inhibition of casein kinase 1δ/εimproves cognitive-affective behavior and reduces amyloid load in the APP-PS1 mouse model of Alzheimer’s disease

Scientific Reports ◽

10.1038/s41598-019-50197-x ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

S. Sundaram ◽

S. Nagaraj ◽

H. Mahoney ◽

A. Portugues ◽

W. Li ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Prefrontal Cortex ◽

Casein Kinase ◽

Behavioral Correlates ◽

Casein Kinase 1 ◽

Model Of Alzheimer’S Disease ◽

Short Period ◽

Amyloid Load ◽

Dependent Tasks

Abstract Circadian rhythm disruption is one of the earliest biomarkers of Alzheimer’s disease (AD), and there exists a bidirectional relationship by which dysfunctions in the circadian clock drive AD pathology and AD pathology drives circadian dysfunction. Casein kinase 1 (CK1) isoforms ε and δ, key circadian regulators, are significantly upregulated in AD and may contribute to AD pathogenesis. In the current studies, we have examined how inhibition of CK1ε/δ with PF-670462 (at 10 mg/kg, δ isoform selective, or 30 mg/kg, δ and ε selective) impacts regional Aβ and circadian gene expression in 10–13 month old APP-PS1 mice and nontransgenic controls. We have also assessed circadian, cognitive, and affective behavioral correlates of these neural changes. At baseline, APP-PS1 mice showed a short period, as well as impaired cognitive performance in both prefrontal cortex and hippocampus-dependent tasks. Both doses of PF-670462 lengthened the period and improved affect, whereas only the higher dose improved cognition. Further, PF-670462 treatment produced a dose-dependent reduction in amyloid burden – overall Aβ signal decreased in all three areas; in the prefrontal cortex and hippocampus, PF-670462 also reduced plaque size. Together, these findings support chronotherapy as a potential tool to improve behavior in AD.

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Immunohistochemical Detection of Receptor-Associated Protein in Normal Human Brain and Alzheimer's Disease

Pathology Research International ◽

10.4061/2010/173496 ◽

2010 ◽

Vol 2010 ◽

pp. 1-5 ◽

Cited By ~ 2

Author(s):

John Provias ◽

Brian Jeynes

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

White Matter ◽

Brain Cortex ◽

Matched Control ◽

Immunohistochemical Detection ◽

Membrane Expression ◽

Receptor Associated Protein ◽

Normal Human ◽

Human Autopsy

This study is one of the few to characterize immunohistochemically the distribution and localization of Receptor-Associated Protein (RAP) in human autopsy brain. The results show prominent cortical neuronal localization. RAP is clearly identified in large neuronal dendritic/axonal processes. RAP is expressed in both large pyramidal and smaller interneurons. Occasional, much less frequent RAP is detectable in glial cells in white matter, which appear to be predominantly astrocytic. Although RAP is detectable immunohistochemically in Alzheimer's disease autopsy brain, the level of expression appears significantly reduced relative to age-matched control brains. These results suggest, at the immunohistochemical level, that there is a reduction of RAP protein in Alzheimer's disease brain (cortex). In terms of Alzheimer's disease pathophysiology, a reduction of neuronal RAP could then lead to reduced membrane expression of LRP, since RAP has also been shown to be an LRP antagonist.

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