Skip to main content Accessibility help

Genome-wide RNA sequencing analysis reveals that IGF-2 attenuates memory decline, oxidative stress and amyloid plaques in an Alzheimer’s disease mouse model (AD) by activating the PI3K/AKT/CREB signaling pathway

  • Lei Xia (a1), Xiangyu Zhu (a2), Ying Zhao (a3), Guang Yang (a3), Xiaohua Zuo (a4), Peng Xie (a5), Chun Chen (a6) and Qiu Han (a3)...



Alzheimer’s Disease (AD), characterized by deficits in memory and cognition and by behavioral impairment, is a progressive neurodegenerative disorder that influences more than 47 million people worldwide. Currently, no available drug is able to stop AD progression. Therefore, novel therapeutic strategies need to be investigated.


We analyzed the RNA sequencing data (RNA-seq) derived from the Gene Expression Omnibus (GEO) database to identify the differentially expressed mRNAs in AD. The AD mouse model Tg2576 was used to verify the effects of IGF-2. The Morris Water Maze was administered to test the role of IGF-2 in memory consolidation. In addition, we quantified cell apoptosis by the TUNEL assay. The levels of amyloid plaques and the levels of Aβ40 and Aβ42 in the hippocampus were also determined by immunohistochemistry and ELISA, respectively.


RNA-seq analysis revealed that IGF-2 was remarkably reduced in AD. The expression of the upstream genes PI3K and AKT and the downstream gene CREB in the PI3K signaling pathway was significantly increased in the hippocampus of Tg2576 mice cells treated with IGF-2. The Morris water maze test showed that IGF-2 improved memory consolidation in Tg2576 mice. The activity of caspase-3 was decreased in Tg2576 mice treated with IGF-2. Amyloid plaques in the hippocampus were reduced, and the levels of Aβ40 and Aβ42 were decreased. The above effects of IGF-2 on AD were blocked when the PI3K signaling pathway inhibitor wortmannin was added.


IGF-2 attenuates memory decline, oxidative stress, cell apoptosis and amyloid plaques in the AD mouse model Tg2576 by activating the PI3K/AKT/CREB signaling pathway.


Corresponding author

Correspondence should be addressed to: Chun Chen, Department of Neurology, Hongze Huaian District People’s Hospital, No.102 Dongfeng Road, Hongze District, Huaian 223100, Jiangsu, China. Phone: +86 0517-87283416. Email:
Qiu Han, Department of Neurology, The Second People’s Hospital of Huaian, the Affiliated Huai’an Hospital of Xuzhou Medical University, No.62 South Huaihai Road, Huaian 223002, Jiangsu, China. Phone: +86 0517-80871771. Email:


Hide All

These authors contributed equally to this work.



Hide All
Aberg, D. et al. (2015). Increased cerebrospinal fluid level of insulin-like growth factor-II in male patients with Alzheimer’s disease. Journal of Alzheimers Disease, 48, 637646. doi: 10.3233/JAD-150351.
Alzheimer’s, A. (2016). 2016 Alzheimer’s disease facts and figures. Alzheimers & Dementia, 12, 459509.
Axelsen, P. H., Komatsu, H. and Murray, I. V. (2011). Oxidative stress and cell membranes in the pathogenesis of Alzheimer’s disease. Physiology (Bethesda), 26, 5469. doi: 10.1152/physiol.00024.2010.
Bracko, O. et al. (2012). Gene expression profiling of neural stem cells and their neuronal progeny reveals IGF2 as a regulator of adult hippocampal neurogenesis. Journal of Neuroscience, 32, 33763387. doi: 10.1523/JNEUROSCI.4248-11.2012.
Camargo, L. C. et al. (2018). Peptides isolated from animal venom as a platform for new therapeutics for the treatment of Alzheimer’s disease. Neuropeptides, 67, 7986. doi: 10.1016/j.npep.2017.11.010.
Chan, T. K. et al. (2016). House dust mite-induced asthma causes oxidative damage and DNA double-strand breaks in the lungs. Journal of Allergy and Clinical Immunology, 138, 8496 e81. doi: 10.1016/j.jaci.2016.02.017.
Chen, D. Y. et al. (2011). A critical role for IGF-II in memory consolidation and enhancement. Nature, 469, 491497. doi: 10.1038/nature09667.
Cline, B. H. et al. (2012). The neuronal insulin sensitizer dicholine succinate reduces stress-induced depressive traits and memory deficit: possible role of insulin-like growth factor 2. BMC Neuroscience, 13, 110. doi: 10.1186/1471-2202-13-110.
Corriveau, R. A. et al. (2017). Alzheimer’s disease-related dementias summit 2016: National research priorities. Neurology, 89, 23812391. doi: 10.1212/WNL.0000000000004717.
Cui, W., Wang, S., Wang, Z., Wang, Z., Sun, C. and Zhang, Y. (2017). Inhibition of PTEN attenuates endoplasmic reticulum stress and apoptosis via activation of PI3K/AKT pathway in Alzheimer’s disease. Neurochemical Research, 42, 30523060. doi: 10.1007/s11064-017-2338-1.
Hertze, J., Nagga, K., Minthon, L. and Hansson, O. (2014). Changes in cerebrospinal fluid and blood plasma levels of IGF-II and its binding proteins in Alzheimer’s disease: an observational study. BMC Neurology, 14, 64. doi: 10.1186/1471-2377-14-64.
Hissin, P. J. and Hilf, R. (1976). A fluorometric method for determination of oxidized and reduced glutathione in tissues. Analytical Biochemistry, 74, 214226.
Hsiao, K. et al. (1996). Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science, 274, 99102.
Kakkar, P., Das, B. and Viswanathan, P. N. (1984). A modified spectrophotometric assay of superoxide dismutase. Indian Journal of Biochemistry & Biophysics, 21, 130132.
Karthivashan, G., Ganesan, P., Park, S. Y., Kim, J. S. and Choi, D. K. (2018). Therapeutic strategies and nano-drug delivery applications in management of ageing Alzheimer’s disease. Drug Delivery, 25, 307320. doi: 10.1080/10717544.2018.1428243.
Kitagishi, Y., Nakanishi, A., Ogura, Y. and Matsuda, S. (2014). Dietary regulation of PI3K/AKT/GSK-3beta pathway in Alzheimer’s disease. Alzheimers Research & Therapy, 6, 35. doi: 10.1186/alzrt265.
Lee, K. W. et al. (2009). Behavioral stress accelerates plaque pathogenesis in the brain of Tg2576 mice via generation of metabolic oxidative stress. Journal of Neurochemistry, 108, 165175. doi: 10.1111/j.1471-4159.2008.05769.x.
Lee, K. Y., Koh, S. H., Noh, M. Y., Kim, S. H. and Lee, Y. J. (2008). Phosphatidylinositol-3-kinase activation blocks amyloid beta-induced neurotoxicity. Toxicology, 243, 4350. doi: 10.1016/j.tox.2007.09.020.
Lisowski, P. et al. (2013). Stress susceptibility-specific phenotype associated with different hippocampal transcriptomic responses to chronic tricyclic antidepressant treatment in mice. BMC Neuroscience, 14, 144. doi: 10.1186/1471-2202-14-144.
Martin-Montanez, E. et al. (2014). Involvement of IGF-II receptors in the antioxidant and neuroprotective effects of IGF-II on adult cortical neuronal cultures. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1842, 10411051. doi: 10.1016/j.bbadis.2014.03.010.
Martins, A. S., Olmos, D., Missiaglia, E. and Shipley, J. (2011). Targeting the insulin-like growth factor pathway in rhabdomyosarcomas: rationale and future perspectives. Sarcoma, 2011, 209736. doi: 10.1155/2011/209736.
Mellott, T. J., Pender, S. M., Burke, R. M., Langley, E. A. and Blusztajn, J. K. (2014). IGF2 ameliorates amyloidosis, increases cholinergic marker expression and raises BMP9 and neurotrophin levels in the hippocampus of the APPswePS1dE9 Alzheimer’s disease model mice. PLoS One, 9, e94287. doi: 10.1371/journal.pone.0094287.
Morroni, F., Sita, G., Tarozzi, A., Rimondini, R. and Hrelia, P. (2016). Early effects of Abeta1-42 oligomers injection in mice: Involvement of PI3K/Akt/GSK3 and MAPK/ERK1/2 pathways. Behavioural Brain Research, 314, 106115. doi: 10.1016/j.bbr.2016.08.002.
Ohkawa, H., Ohishi, N. and Yagi, K. (1979). Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Analytical Biochemistry, 95, 351358.
Ouchi, Y. et al. (2013). Reduced adult hippocampal neurogenesis and working memory deficits in the Dgcr8-deficient mouse model of 22q11.2 deletion-associated schizophrenia can be rescued by IGF2. Journal of Neuroscience, 33, 94089419. doi: 10.1523/JNEUROSCI.2700-12.2013.
Pascual-Lucas, M. et al. (2014). Insulin-like growth factor 2 reverses memory and synaptic deficits in APP transgenic mice. EMBO Molecular Medicine, 6, 12461262. doi: 10.15252/emmm.201404228.
Phillips, J. S. et al. (2018). Neocortical origin and progression of gray matter atrophy in nonamnestic Alzheimer’s disease. Neurobiology of Aging, 63, 7587. doi: 10.1016/j.neurobiolaging.2017.11.008.
Rivera, E. J., Goldin, A., Fulmer, N., Tavares, R., Wands, J. R. and de la Monte, S. M. (2005). Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: link to brain reductions in acetylcholine. Journal of Alzheimers Disease, 8, 247268.
Scheckel, C. et al. (2016). Regulatory consequences of neuronal ELAV-like protein binding to coding and non-coding RNAs in human brain. Elife, 5, e10421. doi: 10.7554/eLife.10421.
Stern, S. A., Kohtz, A. S., Pollonini, G. and Alberini, C. M. (2014). Enhancement of memories by systemic administration of insulin-like growth factor II. Neuropsychopharmacology, 39, 21792190. doi: 10.1038/npp.2014.69.
Stewart, S., Cacucci, F. and Lever, C. (2011). Which memory task for my mouse? A systematic review of spatial memory performance in the Tg2576 Alzheimer’s mouse model. Journal of Alzheimers Disease, 26, 105126. doi: 10.3233/JAD-2011-101827.
Wang, H. and Joseph, J. A. (1999). Quantifying cellular oxidative stress by dichlorofluorescein assay using microplate reader. Free Radical Biology and Medicine, 27, 612616.
Wang, Y., MacDonald, R. G., Thinakaran, G. and Kar, S. (2017). Insulin-like growth factor-II/cation-independent mannose 6-phospate receptor in neurodegenerative diseases. Molecular Neurobiology, 54, 26362658. doi: 10.1007/s12035-016-9849-7.
Wu, X. L., Pina-Crespo, J., Zhang, Y. W., Chen, X. C. and Xu, H. X. (2017). Tau-mediated neurodegeneration and potential implications in diagnosis and treatment of Alzheimer’s disease. Chinese Medical Journal (Engl), 130, 29782990. doi: 10.4103/0366-6999.220313.
Yoon, M. S. and Chen, J. (2008). PLD regulates myoblast differentiation through the mTOR-IGF2 pathway. Journal of Cell Science, 121, 282289. doi: 10.1242/jcs.022566.
Zhang, B. et al. (2016). Neuroprotective effects of salidroside through PI3K/Akt pathway activation in Alzheimer’s disease models. Drug Design Development and Therapy, 10, 13351343. doi: 10.2147/DDDT.S99958.



Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed