Involvement of CRMP2 Phosphorylation in Amyloid Beta-induced Tau Phosphorylation of Hippocampal Neurons in Alzheimer's Disease Mouse Model

Overview

Journal Mol Neurobiol

Date 2025 Feb 1

PMID 39891817

Authors

Daisuke Noguchi

Naoto Watamura

Miyu Nikkuni

Takaomi C Saido

Yoshio Goshima

Toshio Ohshima

Affiliations

Soon will be listed here.

Abstract

Alzheimer's disease (AD) is the most common form of dementia, characterized by amyloid-β (Aβ) deposition and the formation of neurofibrillary tangles composed of hyperphosphorylated tau. Collapsin response mediator protein 2 (CRMP2), a microtubule (MT)-binding protein, regulates MT dynamics and is phosphorylated at Ser522 by cyclin-dependent kinase 5. Previous studies have shown increased CRMP2 phosphorylation at Ser522 (CRMP2-pSer522) in early AD stages and AD mouse models, where it colocalizes with phosphorylated tau. However, the role of CRMP-pSer522 in AD pathology remains unclear. In this study, we generated double transgenic mice by crossing tau Tg (PS19) mice and CRMP2 S522A knock-in (CRMP2KI) mice, in which S522 of CRMP2 was replaced with alanine to create a phospho-defective model. No significant change in tau phosphorylation was observed in the hippocampus of tau Tg; CRMP2KI mice compared to tau Tg littermates. However, when Aβ25-35 oligomers were injected into the hippocampus, tau phosphorylation was significantly reduced in Aβ-injected tau Tg; CRMP2KI mice compared to Aβ-injected tau Tg controls. These findings suggest that CRMP2 phosphorylation at Ser522 promotes Aβ-induced tau phosphorylation in this mouse model of AD.

References

Bloom G . Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. 2014; 71(4):505-8. DOI: 10.1001/jamaneurol.2013.5847. View

Goedert M, Crowther R, Garner C . Molecular characterization of microtubule-associated proteins tau and MAP2. Trends Neurosci. 1991; 14(5):193-9. DOI: 10.1016/0166-2236(91)90105-4. View

Gong C, Liu F, Grundke-Iqbal I, Iqbal K . Post-translational modifications of tau protein in Alzheimer's disease. J Neural Transm (Vienna). 2004; 112(6):813-38. DOI: 10.1007/s00702-004-0221-0. View

Martin L, Latypova X, Terro F . Post-translational modifications of tau protein: implications for Alzheimer's disease. Neurochem Int. 2011; 58(4):458-71. DOI: 10.1016/j.neuint.2010.12.023. View

Neddens J, Temmel M, Flunkert S, Kerschbaumer B, Hoeller C, Loeffler T . Phosphorylation of different tau sites during progression of Alzheimer's disease. Acta Neuropathol Commun. 2018; 6(1):52. PMC: 6027763. DOI: 10.1186/s40478-018-0557-6. View

Barthelemy N, Li Y, Joseph-Mathurin N, Gordon B, Hassenstab J, Benzinger T . A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer's disease. Nat Med. 2020; 26(3):398-407. PMC: 7309367. DOI: 10.1038/s41591-020-0781-z. View

Oddo S, Caccamo A, Kitazawa M, Tseng B, LaFerla F . Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease. Neurobiol Aging. 2003; 24(8):1063-70. DOI: 10.1016/j.neurobiolaging.2003.08.012. View

Huang H, Jiang Z . Accumulated amyloid-beta peptide and hyperphosphorylated tau protein: relationship and links in Alzheimer's disease. J Alzheimers Dis. 2009; 16(1):15-27. DOI: 10.3233/JAD-2009-0960. View

Chong-Shan Shi , Shenderov K, Huang N, Kabat J, Abu-Asab M, Fitzgerald K . Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol. 2012; 13(3):255-63. PMC: 4116819. DOI: 10.1038/ni.2215. View

10.

Dani M, Wood M, Mizoguchi R, Fan Z, Walker Z, Morgan R . Microglial activation correlates in vivo with both tau and amyloid in Alzheimer's disease. Brain. 2018; 141(9):2740-2754. DOI: 10.1093/brain/awy188. View

11.

Kraft A, Hu X, Yoon H, Yan P, Xiao Q, Wang Y . Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice. FASEB J. 2012; 27(1):187-98. PMC: 3528309. DOI: 10.1096/fj.12-208660. View

12.

van der Kant R, Goldstein L, Ossenkoppele R . Amyloid-β-independent regulators of tau pathology in Alzheimer disease. Nat Rev Neurosci. 2019; 21(1):21-35. DOI: 10.1038/s41583-019-0240-3. View

13.

Mattsson-Carlgren N, Andersson E, Janelidze S, Ossenkoppele R, Insel P, Strandberg O . Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer's disease. Sci Adv. 2020; 6(16):eaaz2387. PMC: 7159908. DOI: 10.1126/sciadv.aaz2387. View

14.

Fukata Y, Itoh T, Kimura T, Menager C, Nishimura T, Shiromizu T . CRMP-2 binds to tubulin heterodimers to promote microtubule assembly. Nat Cell Biol. 2002; 4(8):583-91. DOI: 10.1038/ncb825. View

15.

Gu Y, Hamajima N, Ihara Y . Neurofibrillary tangle-associated collapsin response mediator protein-2 (CRMP-2) is highly phosphorylated on Thr-509, Ser-518, and Ser-522. Biochemistry. 2000; 39(15):4267-75. DOI: 10.1021/bi992323h. View

16.

Watamura N, Toba J, Yoshii A, Nikkuni M, Ohshima T . Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer's disease model mice: Involvement of Cdk5 phosphorylation and the effect of ATRA treatment. J Neurosci Res. 2015; 94(1):15-26. DOI: 10.1002/jnr.23674. View

17.

Cole A, Noble W, van Aalten L, Plattner F, Meimaridou R, Hogan D . Collapsin response mediator protein-2 hyperphosphorylation is an early event in Alzheimer's disease progression. J Neurochem. 2007; 103(3):1132-44. DOI: 10.1111/j.1471-4159.2007.04829.x. View

18.

Yamashita N, Ohshima T, Nakamura F, Kolattukudy P, Honnorat J, Mikoshiba K . Phosphorylation of CRMP2 (collapsin response mediator protein 2) is involved in proper dendritic field organization. J Neurosci. 2012; 32(4):1360-5. PMC: 6796265. DOI: 10.1523/JNEUROSCI.5563-11.2012. View

19.

Yoshiyama Y, Higuchi M, Zhang B, Huang S, Iwata N, Saido T . Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007; 53(3):337-51. DOI: 10.1016/j.neuron.2007.01.010. View

20.

Isono T, Yamashita N, Obara M, Araki T, Nakamura F, Kamiya Y . Amyloid-β₂₅₋₃₅ induces impairment of cognitive function and long-term potentiation through phosphorylation of collapsin response mediator protein 2. Neurosci Res. 2013; 77(3):180-5. DOI: 10.1016/j.neures.2013.08.005. View