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

Feng, Weixi; Wang, Ze; Hu, Xu; Wu, Ting; Marshall, Charles; Gao, Junying; Xiao, Ming

doi:10.21203/rs.2.19388/v1

Cited by 8 publications

(11 citation statements)

References 54 publications

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“…AQP4 gene knockout signi cantly delays clearance of exogenous Aβ from the brain following intrastriatal injection [23]. Our present and previous studies consistently demonstrate that AQP4 deletion in APP/PS1 mice exacerbates glymphatic clearance impairment and Aβ plaque load [28,31]. Together, these results indicate that AQP4 is vital for glymphatic clearance, thus playing a critical role in regulating the pathological progress of AD.…”

Section: Discussionsupporting

confidence: 83%

“…Cisterna magna injection of uorescent tracer Cisterna magna injection of uorescent tracer was performed as described previously [24,31]. The mice were anesthetized and positioned in a stereotaxic apparatus while the posterior atlanto-occipital membrane was surgically exposed.…”

Section: Morris Water Maze (Mwm) Testmentioning

confidence: 99%

“…APP695swe/PS1-dE9 (APP/PS1) mice are extensively used mouse model of AD with occurrence of Aβassociated long-term memory malfunction from approximately 6-7 months of age, which serves as a hallmark of moderate stage AD [30]. At 3 months old, despite no Aβ plaques, this AD mouse line exhibits a mild activation of astrocytes with slight impairments of AQP4 polarity and glymphatic transport [31,32]. Therefore, we chose the 3-and 7-month-old APP/PS1 mice and AQP4 −/− /APP/PS1 mice to test whether the time-dependent bene t of exercise on Aβ related pathology is dependent on AQP4-mediated glymphatic transport.…”

Section: Introductionmentioning

confidence: 99%

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Beneficial effects of voluntary exercise therapy on an Alzheimer’s mouse model are dependent on aquaporin 4-mediated glymphatic transport

Liu

Feng

et al. 2020

Preprint

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Background: Epidemiological and clinical evidence suggest there is an effective time window for the ability of exercise to slow the progression of Alzheimer's disease (AD). Astrocyte aquaporin-4 (AQP4) dependent glymphatic transport is necessary for clearance of extracellular amyloid-β (Aβ) from the brain. The purpose of this study is to explore whether this Aβ clearance mechanism is involved in the time-dependent benefit of exercise on Aβ related pathology. Method: 3- and 7-month-old male wild type (WT) mice, APP695swe/PS1-dE9 (APP/PS1) mice and AQP4 knockout (AQP4−/−)/APP/PS1 mice received voluntary wheel exercise intervention for 2 months, followed by behavioral and pathological analyses.Results: 9-month-old APP/PS1 mice showed enhanced reactive astrogliosis, accompanied with widespread loss of perivascular AQP4 polarization, when compared to 5-month-old APP/PS1 mice. Voluntary exercise improved AQP4 polarity and glymphatic transport, reduced glial inflammation and brain Aβ plaque load, plus alleviated synapse protein loss and cognitive deficits in 5-month-old, but not 9-month-old, APP/PS1 mice. Exercise intervention did not mitigate glymphatic transport dysfunction, Aβ accumulation and cognitive impairment in AQP4−/−/APP/PS1 mice at 5 or 9 months of age. Conclusion: These results have revealed that AQP4-dependent glymphatic transport is an influential factor in the timeliness of voluntary exercise ability to alleviate Aβ pathology, potentially offering a new target for the early prevention of the disease.

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Section: Discussionsupporting

confidence: 83%

Section: Morris Water Maze (Mwm) Testmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Beneficial effects of voluntary exercise therapy on an Alzheimer’s mouse model are dependent on aquaporin 4-mediated glymphatic transport

Liu

Feng

et al. 2020

Preprint

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“…CSF-based clearance could account for 25% of Aβ clearance from the mouse brain suggesting that glymphatic function is a significant player in maintaining Aβ homeostasis 55,56 . Expanding links have been made in rodents between ageing and impaired glymphatic function and this fits with the hypothesis that lack of glymphatic function contributes to neurodegeneration 11,20 .…”

Section: Discussionmentioning

confidence: 99%

Glymphatic function in the gyrencephalic brain

Shanbhag

Lundgaard

2020

Preprint

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Identification of the perivascular compartment as the point of exchange between cerebrospinal fluid (CSF) and interstitial fluid mediating solute clearance in the brain, named the glymphatic system, has emerged as an important clearance pathway for neurotoxic peptides such as amyloid-beta. However, the foundational science of the glymphatic system is based on rodent studies. Here we investigated whether the glymphatic system exists in a large mammal with a highly gyrified brain. CSF penetration into the brain via perivascular pathways, a hallmark of glymphatic function, was seen throughout the gyrencephalic cortex and subcortical structures, validating the conservation of the glymphatic system in a large mammal. Macroscopic CSF tracer distribution followed the sulci and fissures showing that the gyri enhance CSF dispersion. Three-dimensional renditions from light sheet microscopy showed that CSF influx through perivascular spaces was 4-fold more extensive in the pig brain than in mice. This demonstrates the existence of an advanced solute transport system in the gyrencephalic brain that could be utilised therapeutically for enhancing waste clearance.

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“…In effect, it was shown that glymphatic transport was affected in both young and old APP/PS1 mice compared to wild-type littermates (Peng et al 2016). Further, Xu et al showed that deletion of AQP4 in APP/PS1 mice resulted in aggravation of amyloid-β accumulation and memory impairment (Xu et al 2015; Feng et al 2020). In addition, the perivascular localisation of AQP4 channels is postulated to be essential in maintaining the efficacy of the GS and has been shown to be declining with age (Kress et al 2014), but to be also related to certain stages of AD pathology (Zeppenfeld et al 2017; Yang et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Dynamics of brain-fluid circulation are altered in the mature-onset Tet-off APP mouse model of amyloidosis

Ben-Nejma

Keliris

Vanreusel

et al. 2022

Preprint

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Alzheimer's disease (AD), the most common type of dementia, is an incurable brain disorder characterised by the progressive build-up of toxic amyloid-beta (Aβ) and tau protein aggregates. AD gradually inflicts cognitive functions of an individual such as memory, thinking, reasoning, and language by degrading synaptic function and the integrity of neuronal networks. It has been recently suggested that the efficacy of different brain-clearance systems like the glymphatic system (GS), involved in the removal of toxic waste and homeostatic balance, plays a key role in the pathology of AD. Moreover, the observed coupling between brain fluid movement and global brain activity implies that an alteration of the neuronal network integrity can impact brain fluid circulation throughout the brain and thereby the efficacy of the GS. Here, we investigated the dynamics of brain fluid circulation in Tet-Off APP (AD) mice, a mature-onset model of amyloidosis in which we have recently shown a deterioration of neuronal network integrity by resting-state fMRI. By utilizing dynamic contrast enhanced-MRI and gadoteric acid (Gd-DOTA) T1 contrast agent injected into the cisterna magna, we demonstrated that brain fluid exchange was significantly altered in 14-month-old AD mice compared to control littermates. More specifically, AD mice showed higher Gd-DOTA accumulation in areas proximal to the injection cite and computational modeling of time courses demonstrated significantly lower inflow time constants relative to the controls. Immunohistochemistry demonstrated abundant amyloid plaque burden in the forebrain of the AD group coinciding with extensive astrogliosis and microgliosis. The neuroinflammatory responses were also found in plaque-devoid regions, potentially impacting brain fluid circulation.

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

Cited by 8 publications

References 54 publications

Beneficial effects of voluntary exercise therapy on an Alzheimer’s mouse model are dependent on aquaporin 4-mediated glymphatic transport

Beneficial effects of voluntary exercise therapy on an Alzheimer’s mouse model are dependent on aquaporin 4-mediated glymphatic transport

Glymphatic function in the gyrencephalic brain

Dynamics of brain-fluid circulation are altered in the mature-onset Tet-off APP mouse model of amyloidosis

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