RPS23RG1 Reduces Aβ Oligomer-induced Synaptic and Cognitive Deficits

Overview

Journal Sci Rep

Specialty Science

Date 2016 Jan 7

PMID 26733416

Citations 6

Authors

Li Yan

Yaomin Chen

Wubo Li

Xiumei Huang

Hedieh Badie

Fan Jian

Timothy Huang

Yingjun Zhao

Stanley N Cohen

Limin Li

Yun-Wu Zhang

Huanmin Luo

Shichun Tu

Huaxi Xu

Affiliations

Soon will be listed here.

Abstract

Alzheimer's disease (AD) is the most common form of dementia in the elderly. It is generally believed that β-amyloidogenesis, tau-hyperphosphorylation, and synaptic loss underlie cognitive decline in AD. Rps23rg1, a functional retroposed mouse gene, has been shown to reduce Alzheimer's β-amyloid (Aβ) production and tau phosphorylation. In this study, we have identified its human homolog, and demonstrated that RPS23RG1 regulates synaptic plasticity, thus counteracting Aβ oligomer (oAβ)-induced cognitive deficits in mice. The level of RPS23RG1 mRNA is significantly lower in the brains of AD compared to non-AD patients, suggesting its potential role in the pathogenesis of the disease. Similar to its mouse counterpart, human RPS23RG1 interacts with adenylate cyclase, activating PKA/CREB, and inhibiting GSK-3. Furthermore, we show that human RPS23RG1 promotes synaptic plasticity and offsets oAβ-induced synaptic loss in a PKA-dependent manner in cultured primary neurons. Overexpression of Rps23rg1 in transgenic mice consistently prevented oAβ-induced PKA inactivation, synaptic deficits, suppression of long-term potentiation, and cognitive impairment as compared to wild type littermates. Our study demonstrates that RPS23RG1 may reduce the occurrence of key elements of AD pathology and enhance synaptic functions to counteract oAβ-induced synaptic and cognitive deficits in AD.

Citing Articles

Comment on "Activation of the Omega-3 Fatty Acid Receptor GPR120 Protects against Focal Cerebral Ischemic Injury by Preventing Inflammation and Apoptosis in Mice".

Brown J, Murphy K, OConnell T, Lesne S J Immunol. 2022; 209(7):1229-1233.

PMID: 36167357 PMC: 9756940. DOI: 10.4049/jimmunol.2200151.

Phenazopyridine promotes RPS23RG1/Rps23rg1 transcription and ameliorates Alzheimer-associated phenotypes in mice.

Wang C, Zhang Y, Zhao D, Huo Y, Xie J, Zhang X Neuropsychopharmacology. 2022; 47(12):2042-2050.

PMID: 35821069 PMC: 9556769. DOI: 10.1038/s41386-022-01373-7.

RPS23RG1 Is Required for Synaptic Integrity and Rescues Alzheimer's Disease-Associated Cognitive Deficits.

Zhao D, Meng J, Zhao Y, Huo Y, Liu Y, Zheng N Biol Psychiatry. 2018; 86(3):171-184.

PMID: 30292394 PMC: 6389446. DOI: 10.1016/j.biopsych.2018.08.009.

Inhibition of PKCδ reduces amyloid-β levels and reverses Alzheimer disease phenotypes.

Du Y, Zhao Y, Li C, Zheng Q, Tian J, Li Z J Exp Med. 2018; 215(6):1665-1677.

PMID: 29739836 PMC: 5987914. DOI: 10.1084/jem.20171193.

ER-associated degradation regulates Alzheimer's amyloid pathology and memory function by modulating γ-secretase activity.

Zhu B, Jiang L, Huang T, Zhao Y, Liu T, Zhong Y Nat Commun. 2017; 8(1):1472.

PMID: 29133892 PMC: 5684335. DOI: 10.1038/s41467-017-01799-4.

References

Naj A, Jun G, Beecham G, Wang L, Vardarajan B, Buros J . Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet. 2011; 43(5):436-41. PMC: 3090745. DOI: 10.1038/ng.801. View

Zhao X, Wang W, Tan J, Huang J, Zhang X, Zhang B . Expression of beta-amyloid induced age-dependent presynaptic and axonal changes in Drosophila. J Neurosci. 2010; 30(4):1512-22. PMC: 6633795. DOI: 10.1523/JNEUROSCI.3699-09.2010. View

Terry R, Masliah E, Salmon D, Butters N, DeTeresa R, Hill R . Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991; 30(4):572-80. DOI: 10.1002/ana.410300410. View

Nakanishi N, Tu S, Shin Y, Cui J, Kurokawa T, Zhang D . Neuroprotection by the NR3A subunit of the NMDA receptor. J Neurosci. 2009; 29(16):5260-5. PMC: 2703294. DOI: 10.1523/JNEUROSCI.1067-09.2009. View

Zheng H, Koo E . Biology and pathophysiology of the amyloid precursor protein. Mol Neurodegener. 2011; 6(1):27. PMC: 3098799. DOI: 10.1186/1750-1326-6-27. View

Billings L, Oddo S, Green K, McGaugh J, LaFerla F . Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron. 2005; 45(5):675-88. DOI: 10.1016/j.neuron.2005.01.040. View

Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S . Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science. 1996; 274(5284):99-102. DOI: 10.1126/science.274.5284.99. View

DaRocha-Souto B, Coma M, Perez-Nievas B, Scotton T, Siao M, Sanchez-Ferrer P . Activation of glycogen synthase kinase-3 beta mediates β-amyloid induced neuritic damage in Alzheimer's disease. Neurobiol Dis. 2011; 45(1):425-37. PMC: 3694284. DOI: 10.1016/j.nbd.2011.09.002. View

Taylor S, Kim C, Cheng C, Brown S, Wu J, Kannan N . Signaling through cAMP and cAMP-dependent protein kinase: diverse strategies for drug design. Biochim Biophys Acta. 2007; 1784(1):16-26. PMC: 2561045. DOI: 10.1016/j.bbapap.2007.10.002. View

10.

Li Z, Sheng M . Caspases in synaptic plasticity. Mol Brain. 2012; 5:15. PMC: 3366905. DOI: 10.1186/1756-6606-5-15. View

11.

Yiu A, Rashid A, Josselyn S . Increasing CREB function in the CA1 region of dorsal hippocampus rescues the spatial memory deficits in a mouse model of Alzheimer's disease. Neuropsychopharmacology. 2011; 36(11):2169-86. PMC: 3176558. DOI: 10.1038/npp.2011.107. View

12.

Molokanova E, Akhtar M, Sanz-Blasco S, Tu S, Pina-Crespo J, McKercher S . Differential effects of synaptic and extrasynaptic NMDA receptors on Aβ-induced nitric oxide production in cerebrocortical neurons. J Neurosci. 2014; 34(14):5023-8. PMC: 3972726. DOI: 10.1523/JNEUROSCI.2907-13.2014. View

13.

Delghandi M, Johannessen M, Moens U . The cAMP signalling pathway activates CREB through PKA, p38 and MSK1 in NIH 3T3 cells. Cell Signal. 2005; 17(11):1343-51. DOI: 10.1016/j.cellsig.2005.02.003. View

14.

Kamenetsky M, Middelhaufe S, Bank E, Levin L, Buck J, Steegborn C . Molecular details of cAMP generation in mammalian cells: a tale of two systems. J Mol Biol. 2006; 362(4):623-39. PMC: 3662476. DOI: 10.1016/j.jmb.2006.07.045. View

15.

Shankar G, Li S, Mehta T, Garcia-Munoz A, Shepardson N, Smith I . Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med. 2008; 14(8):837-42. PMC: 2772133. DOI: 10.1038/nm1782. View

16.

Gonzalez G, Montminy M . Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell. 1989; 59(4):675-80. DOI: 10.1016/0092-8674(89)90013-5. View

17.

Kandel E . The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol Brain. 2012; 5:14. PMC: 3514210. DOI: 10.1186/1756-6606-5-14. View

18.

Zhang X, Poschel B, Faul C, Upreti C, Stanton P, Mundel P . Essential role for synaptopodin in dendritic spine plasticity of the developing hippocampus. J Neurosci. 2013; 33(30):12510-8. PMC: 3721850. DOI: 10.1523/JNEUROSCI.2983-12.2013. View

19.

Jin M, Shepardson N, Yang T, Chen G, Walsh D, Selkoe D . Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc Natl Acad Sci U S A. 2011; 108(14):5819-24. PMC: 3078381. DOI: 10.1073/pnas.1017033108. View

20.

Nakanishi N, Ryan S, Zhang X, Khan A, Holland T, Cho E . Synaptic protein α1-takusan mitigates amyloid-β-induced synaptic loss via interaction with tau and postsynaptic density-95 at postsynaptic sites. J Neurosci. 2013; 33(35):14170-83. PMC: 3756761. DOI: 10.1523/JNEUROSCI.4646-10.2013. View