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Chk1 Inhibition Ameliorates Alzheimer’s Disease Pathogenesis and Cognitive Dysfunction Through CIP2A/PP2A Signaling
- Source :
- Neurotherapeutics. 19:570-591
- Publication Year :
- 2022
- Publisher :
- Springer Science and Business Media LLC, 2022.
-
Abstract
- Alzheimer’s disease (AD) is the most common neurodegenerative disease with limited therapeutic strategies. Cell cycle checkpoint protein kinase 1 (Chk1) is a Ser/Thr protein kinase which is activated in response to DNA damage, the latter which is an early event in AD. However, whether DNA damage-induced Chk1 activation participates in the development of AD and Chk1 inhibition ameliorates AD-like pathogenesis remain unclarified. Here, we demonstrate that Chk1 activity and the levels of protein phosphatase 2A (PP2A) inhibitory protein CIP2A are elevated in AD human brains, APP/PS1 transgenic mice, and primary neurons with Aβ treatment. Chk1 overexpression induces CIP2A upregulation, PP2A inhibition, tau and APP hyperphosphorylation, synaptic impairments, and cognitive memory deficit in mice. Moreover, Chk1 inhibitor (GDC0575) effectively increases PP2A activity, decreases tau phosphorylation, and inhibits Aβ overproduction in AD cell models. GDC0575 also reverses AD-like cognitive deficits and prevents neuron loss and synaptic impairments in APP/PS1 mice. In conclusion, our study uncovers a mechanism by which DNA damage-induced Chk1 activation promotes CIP2A-mediated tau and APP hyperphosphorylation and cognitive dysfunction in Alzheimer’s disease and highlights the therapeutic potential of Chk1 inhibitors in AD.
- Subjects :
- Pharmacology
Amyloid beta-Peptides
Intracellular Signaling Peptides and Proteins
Membrane Proteins
Mice, Transgenic
Neurodegenerative Diseases
tau Proteins
Autoantigens
environment and public health
Disease Models, Animal
Mice
enzymes and coenzymes (carbohydrates)
Alzheimer Disease
Checkpoint Kinase 1
Animals
Humans
Cognitive Dysfunction
Pharmacology (medical)
Protein Phosphatase 2
Neurology (clinical)
Phosphorylation
biological phenomena, cell phenomena, and immunity
Signal Transduction
Subjects
Details
- ISSN :
- 18787479 and 19337213
- Volume :
- 19
- Database :
- OpenAIRE
- Journal :
- Neurotherapeutics
- Accession number :
- edsair.doi.dedup.....80d191443ea573b1acf6c0ac1eafcb0b