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

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

FEBS Letters ◽

10.1016/0014-5793(91)80249-3 ◽

1991 ◽

Vol 279 (1) ◽

pp. 55-57 ◽

Cited By ~ 34

Author(s):

M.V. Aksenova ◽

G.Sh. Burbaeva ◽

K.V. Kandror ◽

D.V. Kapkov ◽

A.S. Stepanov

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Brain Cortex ◽

Casein Kinase ◽

Casein Kinase 2

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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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