Locomotor Hyperactivity in the Early-Stage Alzheimer’s Disease-like Pathology of APP/PS1 Mice: Associated with Impaired Polarization of Astrocyte Aquaporin 4

Wang, Tianqi; Chen, Yan; Zou, Ying; Pang, Yingting; He, Xiaohai; Chen, Yali; Liu, Yun; Feng, Weixi; Li, Qian; Shi, Jingping; Ding, Feng; Marshall, Charles; Gao, Junying; Xiao, Ming

doi:10.14336/ad.2022.0219

Cited by 14 publications

(10 citation statements)

References 84 publications

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“…Deletion of the Aqp4 gene exacerbates disinhibition, intraneuronal Aβ load, and glutamatergic neuron activation in APP/PS1 mice. 71 The association of AQP4 polymorphisms with various circadian rhythm disturbances requires further exploration.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study from our group showed that the hyperactive phenotype in APP/PS1 transgenic mice is associated with mislocalization of perivascular AQP4 and glymphatic transport impairment. Deletion of the Aqp4 gene exacerbates disinhibition, intraneuronal Aβ load, and glutamatergic neuron activation in APP/PS1 mice 71 . The association of AQP4 polymorphisms with various circadian rhythm disturbances requires further exploration.…”

Section: Discussionmentioning

confidence: 99%

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The day‐night differences in cognitive and anxiety‐like behaviors of mice after chronic sleep restriction

et al. 2023

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Animal behavioral tests are often conducted during the day. However, rodents are nocturnal animals and are primarily active at night. The aim of this study was to determine whether there are diurnal changes in cognitive and anxiety-like performance of mice following chronic sleep restriction (SR). We also investigated whether this phenotypic difference is related to the diurnal variation of glymphatic clearance of metabolic wastes. Mice received 9-day SR by the use of the modified rotating rod method, followed by the open field, elevated plus maze, and Y-maze tests conducted during the day and at night, respectively. Brain βamyloid (Aβ) and tau protein levels, the polarity of aquaporin4 (AQP4), a functional marker of the glymphatic system, and glymphatic transport ability were also analyzed. SR mice exhibited cognitive impairment and anxiety-like behaviors during the day, but not at night. AQP4 polarity and glymphatic transport ability were higher during the day, with lower Aβ 1-42 , Aβ 1-40 , and P-Tau levels in the frontal cortex. These day-night differences were totally disrupted after SR.These results reveal the diurnal changes in behavioral performance after chronic SR, which may be related to circadian control of AQP4-mediated glymphatic clearance of toxic macromolecules from the brain.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The day‐night differences in cognitive and anxiety‐like behaviors of mice after chronic sleep restriction

et al. 2023

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“…In the α-syntrophin knockout mouse, CSF influx, CSF-ISF flow, and perivenous interstitial fluids efflux were significantly decreased, while Aβ was increased [ 167 ]. Mislocalization of perivascular astrocyte AQP4 and impairment of the glymphatic system have been well identified in AD [ 16 , 169 , 170 , 171 ]. Postmortem cerebral cortex analyses from AD patients found that the loss of immunofluorescence for perivascular AQP4 was associated with misfolded amyloid-β [ 167 , 172 ].…”

Section: Factors That May Indirectly Affect the Efficacy Of Glymphati...mentioning

confidence: 99%

“…Postmortem cerebral cortex analyses from AD patients found that the loss of immunofluorescence for perivascular AQP4 was associated with misfolded amyloid-β [ 167 , 172 ]. The AQP4 channels were also decreased in perivascular reactive astrocytes of the APP/PS1 mice model of AD and aged mice, and the mislocalization was accompanied by a decrease in the transport of a fluorescent tracer as an indicator of lymphatic clearance in brain interstitial space [ 37 , 169 ]. Mislocalization of AQP4 channels on reactive perivascular astrocytes was also reported in mice models of traumatic brain injury (TBI) [ 173 , 174 ].…”

Section: Factors That May Indirectly Affect the Efficacy Of Glymphati...mentioning

confidence: 99%

The Glymphatic System May Play a Vital Role in the Pathogenesis of Hepatic Encephalopathy: A Narrative Review

Sepehrinezhad

Larsen

Ahmadabad

et al. 2023

Cells

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Hepatic encephalopathy (HE) is a neurological complication of liver disease resulting in cognitive, psychiatric, and motor symptoms. Although hyperammonemia is a key factor in the pathogenesis of HE, several other factors have recently been discovered. Among these, the impairment of a highly organized perivascular network known as the glymphatic pathway seems to be involved in the progression of some neurological complications due to the accumulation of misfolded proteins and waste substances in the brain interstitial fluids (ISF). The glymphatic system plays an important role in the clearance of brain metabolic derivatives and prevents aggregation of neurotoxic agents in the brain ISF. Impairment of it will result in aggravated accumulation of neurotoxic agents in the brain ISF. This could also be the case in patients with liver failure complicated by HE. Indeed, accumulation of some metabolic by-products and agents such as ammonia, glutamine, glutamate, and aromatic amino acids has been reported in the human brain ISF using microdialysis technique is attributed to worsening of HE and correlates with brain edema. Furthermore, it has been reported that the glymphatic system is impaired in the olfactory bulb, prefrontal cortex, and hippocampus in an experimental model of HE. In this review, we discuss different factors that may affect the function of the glymphatic pathways and how these changes may be involved in HE.

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“…These genetic mutations have been used to generate mouse models that recapitulate many of the cellular and behavioral phenotypes seen in human disease [ 8 , 9 ]. For example, in the humanized APP/PS1 double transgenic mouse model of AD that contains disease-associated mutations in the genes encoding APP and PSEN1 , mice exhibit progressive Aβ plaque pathology accompanied by behavioral changes, including hyperactivity, deficits in sensorimotor gating, and the impairment of different types of memory [ 10 – 13 ]. These transgenic mouse models have proved useful in investigating the underlying mechanisms that drive disease pathology in the context of familial AD.…”

Section: Introductionmentioning

confidence: 99%

Loss of GDE2 leads to complex behavioral changes including memory impairment

Daudelin,

Westerhaus,

Zhang

et al. 2024

Behav Brain Funct

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Background Alzheimer’s disease (AD) and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) are debilitating neurodegenerative diseases for which there are currently no cures. Familial cases with known genetic causes make up less than 10% of these diseases, and little is known about the underlying mechanisms that contribute to sporadic disease. Accordingly, it is important to expand investigations into possible pathways that may contribute to disease pathophysiology. Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) is a membrane-bound enzyme that acts at the cell surface to cleave the glycosylphosphatidylinositol (GPI)-anchor that tethers distinct proteins to the membrane. GDE2 abnormally accumulates in intracellular compartments in the brain of patients with AD, ALS, and ALS/FTD, indicative of GDE2 dysfunction. Mice lacking GDE2 (Gde2KO) show neurodegenerative changes such as neuronal loss, reduced synaptic proteins and synapse loss, and increased Aβ deposition, raising the possibility that GDE2 disruption in disease might contribute to disease pathophysiology. However, the effect of GDE2 loss on behavioral function and learning/memory has not been characterized. Results Here, we show that GDE2 is expressed throughout the adult mouse brain in areas including the cortex, hippocampus, habenula, thalamus, and amygdala. Gde2KO and WT mice were tested in a set of behavioral tasks between 7 and 16 months of age. Compared to WT, Gde2KO mice display moderate hyperactivity that becomes more pronounced with age across a variety of behavioral tests assessing novelty-induced exploratory activity. Additionally, Gde2KO mice show reduced startle response, with females showing additional defects in prepulse inhibition. No changes in anxiety-associated behaviors were found, but Gde2KOs show reduced sociability. Notably, aged Gde2KO mice demonstrate impaired short/long-term spatial memory and cued fear memory/secondary contextual fear acquisition. Conclusions Taken together, these observations suggest that loss of GDE2 leads to behavioral deficits, some of which are seen in neurodegenerative disease models, implying that loss of GDE2 may be an important contributor to phenotypes associated with neurodegeneration.

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Locomotor Hyperactivity in the Early-Stage Alzheimer’s Disease-like Pathology of APP/PS1 Mice: Associated with Impaired Polarization of Astrocyte Aquaporin 4

Cited by 14 publications

References 84 publications

The day‐night differences in cognitive and anxiety‐like behaviors of mice after chronic sleep restriction

The day‐night differences in cognitive and anxiety‐like behaviors of mice after chronic sleep restriction

The Glymphatic System May Play a Vital Role in the Pathogenesis of Hepatic Encephalopathy: A Narrative Review

Loss of GDE2 leads to complex behavioral changes including memory impairment

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