Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits

Xu, Zhiqiang; Xiao, Na; Chen, Yali; Huang, Huang; Marshall, Charles; Gao, Junying; Cai, Zhiyou; Wu, Ting; Hu, Gang; Xiao, Ming

doi:10.1186/s13024-015-0056-1

Cited by 363 publications

(356 citation statements)

References 64 publications

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“…For example, the water channel AQP-4, predominantly expressed in the end-feet of astrocytes, regulates A␤ accumulation, cerebral amyloid angiopathy, and synapses in APP/PS1 mice . Of note, deletion of AQP-4 has been shown to increase astrocyte atrophy and suppresses LRP1 expression in the astrocytes surrounding A␤ plaques (Yang et al, 2012;Xu et al, 2015). Our results showed that deletion of LRP1 in the astrocytes did not significantly alter the levels of AQP-4, suggesting that AQP-4 may function in the upstream of LRP1 in astrocytes.…”

Section: Lrp1 Ligand Rap (mentioning

confidence: 45%

Astrocytic LRP1 Mediates Brain Aβ Clearance and Impacts Amyloid Deposition

et al. 2017

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Accumulation and deposition of amyloid-␤ (A␤) in the brain represent an early and perhaps necessary step in the pathogenesis of Alzheimer's disease (AD). A␤ accumulation leads to the formation of A␤ aggregates, which may directly and indirectly lead to eventual neurodegeneration. While A␤ production is accelerated in many familial forms of early-onset AD, increasing evidence indicates that impaired clearance of A␤ is more evident in late-onset AD. To uncover the mechanisms underlying impaired A␤ clearance in AD, we examined the role of low-density lipoprotein receptor-related protein 1 (LRP1) in astrocytes. Although LRP1 has been shown to play critical roles in brain A␤ metabolism in neurons and vascular mural cells, its role in astrocytes, the most abundant cell type in the brain responsible for maintaining neuronal homeostasis, remains unclear. Here, we show that astrocytic LRP1 plays a critical role in brain A␤ clearance. LRP1 knockdown in primary astrocytes resulted in decreased cellular A␤ uptake and degradation. In addition, silencing of LRP1 in astrocytes led to downregulation of several major A␤-degrading enzymes, including matrix metalloproteases MMP2, MMP9, and insulin-degrading enzyme. More important, conditional knock-out of the Lrp1 gene in astrocytes in the background of APP/PS1 mice impaired brain A␤ clearance, exacerbated A␤ accumulation, and accelerated amyloid plaque deposition without affecting its production. Together, our results demonstrate that astrocytic LRP1 plays an important role in A␤ metabolism and that restoring LRP1 expression and function in the brain could be an effective strategy to facilitate A␤ clearance and counter amyloid pathology in AD.

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Section: Lrp1 Ligand Rap (mentioning

confidence: 45%

Astrocytic LRP1 Mediates Brain Aβ Clearance and Impacts Amyloid Deposition

et al. 2017

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“…This suggests that unknown abluminal mechanisms may be involved in perivascular AQP4 localization. Mislocalization of AQP4 at the astrocyte endfoot has also been confirmed in several mouse models of AD (32, 65, 66). To further extrapolate the role of perivascular AQP4 localization, a study using the same model of VaD as described above in rats, found that decreased perivascular AQP4 expression persisted up to 6 weeks after microinfarction(30).…”

Section: Glymphatic Systemmentioning

confidence: 67%

Perivascular spaces, glymphatic dysfunction, and small vessel disease

2017

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Cerebral small vessel diseases (SVD) range broadly in etiology but share a remarkably overlapping pathology. Features of SVD including enlarged perivascular spaces and formation of abluminal protein deposits cannot be completely explained by the putative pathophysiology. The recently discovered glymphatic system provides a new perspective to potentially address these gaps. This work provides a comprehensive review of the known factors that regulate glymphatic function and the disease mechanisms underlying glymphatic impairment emphasizing the role that aquaporin-4 (AQP4)-lined perivascular spaces, cerebrovascular pulsatility, and metabolite clearance play in normal CNS physiology. This review also discusses the implications that glymphatic impairment may have on SVD inception and progression with the aim of exploring novel therapeutic targets and highlighting the key questions that remain to be answered.

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“…Interestingly, Aqp4 gene deletion reduced Aβ42-induced astrocyte activation, in vitro (Yang et al, 2012). Recently, it was shown that deletion of Aqp4 in the APP/PS1 mice exacerbates Aβ accumulation in brain and contributes to memory deficits (Xu et al, 2015). Our data are congruent with these studies, but also indicated that soluble Aβ oligomers, a more toxic form of Aβ, may contribute to the suppression of glymphatic activities in aging APP/PS1 mice.…”

Section: Discussionmentioning

confidence: 99%

Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease

Peng

Achariyar

et al. 2016

Neurobiology of Disease

433

393

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Glymphatic transport, defined as cerebrospinal fluid (CSF) peri-arterial inflow into brain, and interstitial fluid (ISF) clearance, is reduced in the aging brain. However, it is unclear whether glymphatic transport affects the distribution of soluble Aβ in Alzheimer’s disease (AD). In wild type mice, we show that Aβ40 (fluorescently labeled Aβ40 or unlabeled Aβ40), was distributed from CSF to brain, via the peri-arterial space, and associated with neurons. In contrast, Aβ42 was mostly restricted to the peri-arterial space due mainly to its greater propensity to oligomerize when compared to Aβ40. Interestingly, pretreatment with Aβ40 in the CSF, but not Aβ42, reduced CSF transport into brain. In APP/PS1 mice, a model of AD, with and without extensive amyloid-β deposits, glymphatic transport was reduced, due to the accumulation of toxic Aβ species, such as soluble oligomers. CSF-derived Aβ40 co-localizes with existing endogenous vascular and parenchymal amyloid-β plaques, and thus, may contribute to the progression of both cerebral amyloid angiopathy and parenchymal Aβ accumulation. Importantly, glymphatic failure preceded significant amyloid-β deposits, and thus, may be an early biomarker of AD. By extension, restoring glymphatic inflow and ISF clearance are potential therapeutic targets to slow the onset and progression of AD.

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Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits

Cited by 363 publications

References 64 publications

Astrocytic LRP1 Mediates Brain Aβ Clearance and Impacts Amyloid Deposition

Astrocytic LRP1 Mediates Brain Aβ Clearance and Impacts Amyloid Deposition

Perivascular spaces, glymphatic dysfunction, and small vessel disease

Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease

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