Tags

Type your tag names separated by a space and hit enter

Microglia prevent beta-amyloid plaque formation in the early stage of an Alzheimer's disease mouse model with suppression of glymphatic clearance.
Alzheimers Res Ther. 2020 10 02; 12(1):125.AR

Abstract

BACKGROUND

Soluble beta-amyloid (Aβ) 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 Aβ 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 Aβ 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 Aβ and apoE, although it did not lead to Aβ plaque deposition. Notably, microglia, but not astrocytes, increased activation and phagocytosis of Aβ 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 Aβ plaques in AQP4-/-/APP/PS1 mice, but not APP/PS1 mice. Moreover, knockdown of apoE reduced intraneuronal Aβ levels in both APP/PS1 mice and AQP4-/-/APP/PS1 mice, indicating an inhibitory effect of apoE on Aβ clearance.

CONCLUSION

The above results suggest that the glymphatic system mediated Aβ and apoE clearance and microglia mediated Aβ degradation synergistically prevent Aβ 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.

Authors+Show Affiliations

Jiangsu Province Key Laboratory of Neurodegeneration, Center for Global Health, Nanjing Medical University, Nanjing, China. Brain Institute, The Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing, China.Jiangsu Province Key Laboratory of Neurodegeneration, Center for Global Health, Nanjing Medical University, Nanjing, China. Brain Institute, The Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing, China.Jiangsu Province Key Laboratory of Neurodegeneration, Center for Global Health, Nanjing Medical University, Nanjing, China. Brain Institute, The Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing, China.Jiangsu Province Key Laboratory of Neurodegeneration, Center for Global Health, Nanjing Medical University, Nanjing, China. Brain Institute, The Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing, China.Department of Neurology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.Department of Physical Therapy, University of Kentucky Center of Excellence in Rural Health, Hazard, KY, USA.Jiangsu Province Key Laboratory of Neurodegeneration, Center for Global Health, Nanjing Medical University, Nanjing, China. gaojunying@njmu.edu.cn. Brain Institute, The Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing, China. gaojunying@njmu.edu.cn.Jiangsu Province Key Laboratory of Neurodegeneration, Center for Global Health, Nanjing Medical University, Nanjing, China. mingx@njmu.edu.cn. Brain Institute, The Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing, China. mingx@njmu.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33008458

Citation

Feng, Weixi, et al. "Microglia Prevent Beta-amyloid Plaque Formation in the Early Stage of an Alzheimer's Disease Mouse Model With Suppression of Glymphatic Clearance." Alzheimer's Research & Therapy, vol. 12, no. 1, 2020, p. 125.
Feng W, Zhang Y, Wang Z, et al. Microglia prevent beta-amyloid plaque formation in the early stage of an Alzheimer's disease mouse model with suppression of glymphatic clearance. Alzheimers Res Ther. 2020;12(1):125.
Feng, W., Zhang, Y., Wang, Z., Xu, H., Wu, T., Marshall, C., Gao, J., & Xiao, M. (2020). Microglia prevent beta-amyloid plaque formation in the early stage of an Alzheimer's disease mouse model with suppression of glymphatic clearance. Alzheimer's Research & Therapy, 12(1), 125. https://doi.org/10.1186/s13195-020-00688-1
Feng W, et al. Microglia Prevent Beta-amyloid Plaque Formation in the Early Stage of an Alzheimer's Disease Mouse Model With Suppression of Glymphatic Clearance. Alzheimers Res Ther. 2020 10 2;12(1):125. PubMed PMID: 33008458.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Microglia prevent beta-amyloid plaque formation in the early stage of an Alzheimer's disease mouse model with suppression of glymphatic clearance. AU - Feng,Weixi, AU - Zhang,Yanli, AU - Wang,Ze, AU - Xu,Hanrong, AU - Wu,Ting, AU - Marshall,Charles, AU - Gao,Junying, AU - Xiao,Ming, Y1 - 2020/10/02/ PY - 2019/12/18/received PY - 2020/09/15/accepted PY - 2020/10/3/entrez PY - 2020/10/4/pubmed PY - 2021/6/25/medline KW - Alzheimer’s disease KW - Aquaporin 4 KW - Glia KW - Glymphatic system KW - β-Amyloid SP - 125 EP - 125 JF - Alzheimer's research & therapy JO - Alzheimers Res Ther VL - 12 IS - 1 N2 - BACKGROUND: Soluble beta-amyloid (Aβ) 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 Aβ 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 Aβ 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 Aβ and apoE, although it did not lead to Aβ plaque deposition. Notably, microglia, but not astrocytes, increased activation and phagocytosis of Aβ 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 Aβ plaques in AQP4-/-/APP/PS1 mice, but not APP/PS1 mice. Moreover, knockdown of apoE reduced intraneuronal Aβ levels in both APP/PS1 mice and AQP4-/-/APP/PS1 mice, indicating an inhibitory effect of apoE on Aβ clearance. CONCLUSION: The above results suggest that the glymphatic system mediated Aβ and apoE clearance and microglia mediated Aβ degradation synergistically prevent Aβ 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. SN - 1758-9193 UR - https://www.unboundmedicine.com/medline/citation/33008458/Microglia_prevent_beta_amyloid_plaque_formation_in_the_early_stage_of_an_Alzheimer's_disease_mouse_model_with_suppression_of_glymphatic_clearance_ L2 - https://alzres.biomedcentral.com/articles/10.1186/s13195-020-00688-1 DB - PRIME DP - Unbound Medicine ER -