Microglia prevent beta-amyloid plaque formation in the early stage of an Alzheimer's disease mouse model with suppression of glymphatic clearance

被引:107
作者
Feng, Weixi [1 ,2 ]
Zhang, Yanli [1 ,2 ]
Wang, Ze [1 ,2 ]
Xu, Hanrong [1 ,2 ]
Wu, Ting [3 ]
Marshall, Charles [4 ]
Gao, Junying [1 ,2 ]
Xiao, Ming [1 ,2 ]
机构
[1] Nanjing Med Univ, Ctr Global Hlth, Jiangsu Prov Key Lab Neurodegenerat, Nanjing, Peoples R China
[2] Nanjing Med Univ, Affiliated Nanjing Brain Hosp, Brain Inst, Nanjing, Peoples R China
[3] Nanjing Med Univ, Affiliated Hosp 1, Dept Neurol, Nanjing, Jiangsu, Peoples R China
[4] Univ Kentucky, Ctr Excellence Rural Hlth, Dept Phys Therapy, Hazard, KY USA
基金
中国国家自然科学基金;
关键词
Alzheimer's disease; Aquaporin; 4; beta-Amyloid; Glia; Glymphatic system; A-BETA; APOLIPOPROTEIN-E; BRAIN; AQUAPORIN-4; ACCUMULATION; CELLS; APOE; TRANSPORT; PEPTIDE; PROTEIN;
D O I
10.1186/s13195-020-00688-1
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Background: Soluble beta-amyloid (A beta) can be cleared from the brain through various mechanisms including enzymatic degradation, glial cell phagocytosis, transport across the blood-brain barrier, and glymphatic clearance. However, the relative contribution of each clearance system and their compensatory effects in delaying the pathological process of Alzheimer's disease (AD) are currently unknown. Methods: Fluorescent trace, immunofluorescence, and Western blot analyses were performed to compare glymphatic clearance ability and A beta accumulation among 3-month-old APP695/PS1-dE9 transgenic (APP/PS1) mice, wild-type mice, aquaporin 4 knock out (AQP4(-/-)) mice, and AQP4(-/-)/APP/PS1 mice. The consequence of selectively eliminating microglial cells, or downregulating apolipoprotein E (apoE) expression, on A beta burden, was also investigated in the frontal cortex of AQP4(-/-)/APP/PS1 mice and APP/PS1 mice. Results: AQP4 deletion in APP/PS1 mice significantly exaggerated glymphatic clearance dysfunction, and intraneuronal accumulation of A beta and apoE, although it did not lead to A beta plaque deposition. Notably, microglia, but not astrocytes, increased activation and phagocytosis of A beta in the cerebral cortex of AQP4(-/-)/APP/PS1 mice, compared with APP/PS1 mice. Selectively eliminating microglia in the frontal cortex via local injection of clodronate liposomes resulted in deposition of A beta plaques in AQP4(-/-)/APP/PS1 mice, but not APP/PS1 mice. Moreover, knockdown of apoE reduced intraneuronal A beta levels in both APP/PS1 mice and AQP4(-/-)/APP/PS1 mice, indicating an inhibitory effect of apoE on A beta clearance. Conclusion: The above results suggest that the glymphatic system mediated A beta and apoE clearance and microglia mediated A beta degradation synergistically prevent A beta plague formation in the early stages of the AD mouse model. Protecting one or both of them might be beneficial to delaying the onset of AD.
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页数:15
相关论文
共 64 条
[1]   Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation [J].
Achariyar, Thiyagaragan M. ;
Li, Baoman ;
Peng, Weiguo ;
Verghese, Philip B. ;
Shi, Yang ;
McConnell, Evan ;
Benraiss, Abdellatif ;
Kasper, Tristan ;
Song, Wei ;
Takano, Takahiro ;
Holtzman, David M. ;
Nedergaard, Maiken ;
Deane, Rashid .
MOLECULAR NEURODEGENERATION, 2016, 11
[2]   A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules [J].
Aspelund, Aleksanteri ;
Antila, Salli ;
Proulx, Steven T. ;
Karlsen, Tine Veronica ;
Karaman, Sinem ;
Detmar, Michael ;
Wiig, Helge ;
Alitalo, Kari .
JOURNAL OF EXPERIMENTAL MEDICINE, 2015, 212 (07) :991-999
[3]   Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition [J].
Bales, KR ;
Verina, T ;
Dodel, RC ;
Du, YS ;
Altstiel, L ;
Bender, M ;
Hyslop, P ;
Johnstone, EM ;
Little, SP ;
Cummins, DJ ;
Piccardo, P ;
Ghetti, B ;
Paul, SM .
NATURE GENETICS, 1997, 17 (03) :263-264
[4]   Genetic mouse models of brain ageing and Alzheimer's disease [J].
Bilkei-Gorzo, Andras .
PHARMACOLOGY & THERAPEUTICS, 2014, 142 (02) :244-257
[5]   Effects of apolipoprotein E (apoE) isoforms, β-amyloid (Aβ) and apoE/Aβ complexes on protein kinase C-α (PKC-α) translocation and amyloid precursor protein (APP) processing in human SH-SY5Y neuroblastoma cells and fibroblasts [J].
Cedazo-Mínguez, A ;
Wiehager, B ;
Winblad, B ;
Hüttinger, M ;
Cowburn, RF .
NEUROCHEMISTRY INTERNATIONAL, 2001, 38 (07) :615-625
[6]   Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease [J].
Da Mesquita, Sandro ;
Louveau, Antoine ;
Vaccari, Andrea ;
Smirnov, Igor ;
Cornelison, R. Chase ;
Kingsmore, Kathryn M. ;
Contarino, Christian ;
Onengut-Gumuscu, Suna ;
Farber, Emily ;
Raper, Daniel ;
Viar, Kenneth E. ;
Powell, Romie D. ;
Baker, Wendy ;
Dabhi, Nisha ;
Bai, Robin ;
Cao, Rui ;
Hu, Song ;
Rich, Stephen S. ;
Munson, Jennifer M. ;
Lopes, M. Beatriz ;
Overall, Christopher C. ;
Acton, Scott T. ;
Kipnis, Jonathan .
NATURE, 2018, 560 (7717) :185-+
[7]   The Cellular Phase of Alzheimer's Disease [J].
De Strooper, Bart ;
Karran, Eric .
CELL, 2016, 164 (04) :603-615
[8]   Sex- and region-specific alterations of basal amino acid and monoamine metabolism in the brain of aquaporin-4 knockout mice [J].
Fan, Y ;
Zhang, J ;
Sun, XL ;
Gao, L ;
Zeng, XN ;
Ding, JH ;
Cao, C ;
Niu, L ;
Hu, G .
JOURNAL OF NEUROSCIENCE RESEARCH, 2005, 82 (04) :458-464
[9]   Apolipoprotein E4 Alters Astrocyte Fatty Acid Metabolism and Lipid Droplet Formation [J].
Farmer, Brandon C. ;
Kluemper, Jude ;
Johnson, Lance A. .
CELLS, 2019, 8 (02)
[10]  
Fryer JD, 2003, J NEUROSCI, V23, P7889