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.
Highlights
Alzheimer’s disease (AD) is a common neurodegenerative disorder accompanied by progressive development of cognitive impairments and synaptic dysfunction
To confirm the DNA damage and checkpoint protein kinase 1 (Chk1) activation in AD brains, we detected the protein levels of DNA damage markers and Chk1 and active forms of Chk1 (Chk1 phosphorylated at S345, S317, and S296), as well as Cancerous inhibitor of PP2A (CIP2A) levels in brains of AD patients and APP/ PS1 transgenic mice
We found that the levels of CIP2A and active Chk1 (Chk1-S345, Chk1-S317, Chk1-S296) were elevated in AD human brains and APP/PS1 transgenic mice (Fig. 1a, b, c, d)
Summary
Alzheimer’s disease (AD) is a common neurodegenerative disorder accompanied by progressive development of cognitive impairments and synaptic dysfunction. The major components of NFTs and SPs are hyperphosphorylated tau and Aβ, both of which have toxic effects on synaptic function and induce the damage and loss of neurons in the AD brain. CIP2A is an oncoprotein proved to be upregulated in a variety of peripheral tumors, and promotes tumor cell growth through inhibiting the dephosphorylation of PP2A substrates which are involved in cancer development [3, 4]. We and others showed that CIP2A was expressed in the brain of humans and mice. Our previous research indicated that in the brain of AD human and transgenic mice, the expression of CIP2A increased and overexpression of CIP2A induced tau and APP hyperphosphorylation through inhibiting PP2A, causing cognitive and memory impairment and synaptic dysfunction [5]. Specific overexpression of CIP2A in mouse brain astrocytes resulted in reactive astrogliosis, which promote synaptic degeneration and cognitive deficits [6]. The mechanism of CIP2A upregulation in AD remains unclear
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