Research progress of Wnt/LRP6 signaling pathway on synaptic function in alzheimer′s Disease
WANG Su1 LI Yiping1 XIE Ning2
1.Graduate College, Heilongjiang University of Chinese Medicine, Heilongjiang Province, Harbin 150040, China;
2.Basic Medical College, Heilongjiang University of Chinese Medicine, Heilongjiang Province, Harbin 150040, China
Abstract:Alzheimer′s disease (AD) is one of the most common dementias currently. AD is characterized by the formation of senile plaques by the deposition of β amyloid in the brain, and the main pathological manifestations of neurofibrillary tangles and loss of neurons caused by excessive phosphorylation of Tau protein, accompanied by neuroinflammatory changes and cognitive impairment. There have been extensive studies to prove that synaptic dysfunction and synaptic loss are pathological manifestations of AD in the early stage. Aβ has direct toxic effect on the synapse, but the type of signaling pathway through which Aβ affects the synapse needs further study. The Wnt/β-catenin signaling pathway plays an important role in the functional and morphological integrity of synaptic connections in the adult brain through the common wnt-lrp6 locus. On this basis, this paper explores the underlying mechanism of AD susceptibility in order to reveal new therapeutic targets and methods.
王素1 李一平1 谢宁2. Wnt/LRP6信号通路对阿尔茨海默病突触功能影响的研究进展[J]. 中国医药导报, 2020, 17(8): 33-35,47.
WANG Su1 LI Yiping1 XIE Ning2. Research progress of Wnt/LRP6 signaling pathway on synaptic function in alzheimer′s Disease. 中国医药导报, 2020, 17(8): 33-35,47.
[1] Emily H,Lucy Wang. Alzheimer′s Disease and Overview of Dementia [M].Springer New York:2019.
[2] Wyss-Coray T. Ageing,neurodegeneration and brain rejuvenation [J]. Nature,2016,539(7628):180-186.
[3] Dennis J,Selkoe. Alzheimer′s disease is a synaptic failure [J].Science,2002,298(5594):789-791.
[4] Nusse R,Clevers H. Wnt/β-catenin signaling,disease,and emerging therapeutic modalities[J]. Cell,2017,169(6):985-999.
[5] Park M,Shen K. WNT′s in synapse formation and neuronalcircuitry [J]. EMBO J,2012,31(12):2697-2704.
[6] Stamatakou E,Salinas PC. Postsynaptic assembly:a role for Wnt signaling [J]. Dev Neur,2014,74(8):818-827.
[7] Ciani L,Marzo A,Boyle K,et al. Wnt signaling tunes neurotransmitter release by directly targeting Synaptotagmin-1 [J]. Nat Commun,2015,6:8302.
[8] Ciani L,Boyle KA,Dickins E,et al. Wnt7 a signaling promotes dendritic spine growth and synaptic strength through Ca2+/Calmodulin-dependent protein kinase Ⅱ [J]. Proc Natl Acad Sci USA, 2011,108(26):10732-10737.
[9] Purro SA,Dickins EM,Salinas PC. The secreted Wnt antagonist Dickkopf-1 is required for amyloid β-mediated synaptic loss. [J]. Neurosci,2012,32(10):3492-3498.
[10] Galli S,Lopes DM,Ammari R,et al. Deficient Wnt signaling triggers striatal synaptic degeneration and impaired motor behaviour in adult mice [J]. Nat Commun,2014,5(2):4992.
[11] Marzo A,Galli S,Lopes D,et al. Reversal of synapse degeneration by restoring wnt signaling in the adult hippocampus [J]. Curr Biol,2016,26(19):2551-2561.
[12] Xu N,Zhou WJ,Wang Y,et al. Hippocampal wnt3a is necessary and sufficient for contextual fear memory acquisition and consolidation [J] Cereb Cortex,2015,25(11):4062-4075.
[13] Forner S,Baglietto-Vargas D,MartiniAC,et al. Synaptic impairment in alzheimer′s disease:adysregulated symphony [J]. Trends Neurosci,2017,40(6):347-357.
[14] MacDonald BT,Tamai K,He X. Wnt/β-catenin signaling:components,mechanisms,and diseases [J]. Dev Cell,2009,17(1):9-26.
[15] 宋志琦,王进,朱婷,等.Wnt-LRP6信号通路激活REST蛋白的表达并发挥神经保护作用[J].中国农业大学学报,2017,22(6):100-108.
[16] Zhou CJ,Borello U,Rubenstein JL,et al. Neuronal production and precursor proliferation defects in the neocortex of mice with loss of function in the canonical Wnt signaling pathway [J]. Neuroscience,2006,142(4):1119-1131.
[17] Sharma K,Choi SY,Zhang Y,et al. High-throughput genetic screen for synaptogenic factors:identification of LRP6 as critical for excitatory synapse development [J]. Cell Rep,2013,142(4):1330-1341.
[18] Liu CC,Tsai CW,Deak F,et al. Deficiency in LRP6-mediated Wnt signaling contributes to synaptic Abnormalities and amyloid pathology in Alzheimer′s disease [J]. Neuron,2014,84(1):63-77.
[19] Lee JH,Cheng R,Rogaeva E,et al. Further examination of the candidate genes in chromosome 12p13 locus for late-onset Alzheimer disease [J]. Neurogenetics,2008,9(2):127-138.
[20] Alarcón MA,Medina MA,Hu Q,et al. A novel functional low-density lipoprotein receptor-related protein 6 gene alternative splice variant is associated with Alzheimer′sdisease [J]. Neurobiol Aging,2013,34(6):1709.eq-18.
[21] González H,Elgueta D,Montoya A,et al. Neuroimmune regulation of microglial activity involved in neuroinflammation and neurodegenerative diseases [J]. J Neuroimmunol,2014,274(1/2):1-13.
[22] Giorgi FS,Saccaro LF,Galgani A,et al. The role of Locus Coeruleus in neuroinflammation occurring in Alzheimer′s disease [J]. Brain Res Bull,2019,153:47-58.
[23] Bronzuoli MR,Iacomino A,Steardo L,et al. Targeting neuroinflammation in Alzheimer′s disease [J]. Inflamm Res,2016,9:199-208.
[24] Ye ZJ,Go GW,Singh R,et al. LRP6 protein regulates low density lipoprotein(LDL)receptor-mediated LDLuptake. [J]. Biol Chem,2012,287(2):1335-1344.
[25] Go GW,Srivastava R,Hernandez-Ono A,et al. The combined hyperlipidemia caused by impaired Wnt-LRP6 signaling is reversed by Wnt3a rescue [J]. Cell Metab,2014, 19(2):209-220.