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

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.

Clinical application of intrathecal gadobutrol for assessment of cerebrospinal fluid tracer clearance to blood

“…Possibly, gadobutrol might be used as a surrogate marker of metabolic by-products excreted via CSF. A significant amount of Aβ isoforms are indeed cleared via CSF; about one-quarter of Aβ is cleared via CSF in rodents ( 50 , 51 ). Tau to some extent passes across the BBB, particularly in the presence of BBB disruption.…”

Multifaceted Role of Matrix Metalloproteinases in Neurodegenerative Diseases: Pathophysiological and Therapeutic Perspectives

“…Some of the theories suggest a fundamental role for reactive microglia close to the amyloid plaques in the CNS. The idea is that reactive microglia produce large amounts of inflammatory chemokines and cytokines, which withstand a prolonged inflammation, eventually leading to neuronal cell death [ 122 ]. Besides the well-known effect of neurotoxicity, Aβ can exhibit indirect proinflammatory activity via the microglial activation, which lead to the secretion of TNFα, NO, and super oxides [ 123 , 124 , 125 ].…”

The Glymphatic System: A Novel Therapeutic Target for Stroke Treatment

“…In addition, microglia enhance astrocytes responses via Toll-like receptor 4 (TLR4) activation under insults, injury, or inflammation in stroke ( Holm et al, 2012 ). Notably, although reactive astrocytes triggered by microglia activation are harmful to their function in the GS, an enhanced uptake and phagocytosis of astrocyte solutes and microglia may offset the impairment of glymphatic clearance ( Feng et al, 2020 ).…”