Mesenchymal stem cells alleviate AQP-4-dependent glymphatic dysfunction and improve brain distribution of antisense oligonucleotides in BACHD mice

Wu, Tengteng; Su, Fengjuan; Feng, Yanqing; Liu, Bin; Li, Ming‐yue; Liang, Fengyin; Li, Ge; Li, Xue‐jiao; Cai, Zhong‐qiong; Pei, Zhong

doi:10.1002/stem.3103

Cited by 32 publications

(23 citation statements)

References 44 publications

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“…While a proinflammatory role of AQP4 is consistent with the early study of Li et al [23], the present findings are not easily reconciled with recent studies suggesting that AQP4 may play an immunosuppressive role in models of MPTP and LPS induced neuroinflammation [62,63]. The latter studies reported that Aqp4 −/− mice treated with MPTP or LPS revealed an increased microglial inflammatory response and a more pronounced loss of TH-neurons in the SN, compared with WT mice.…”

Section: Discussionsupporting

confidence: 59%

“…The list of neurological conditions in which AQP4 might play a pathophysiological role includes epilepsy [15,16] and neurodegenerative diseases, such as Alzheimer's disease (AD) [17][18][19][20], amyotrophic lateral sclerosis (ALS) [21,22], Huntington's disease (HD) [23] and spongiform encephalopathy (SE) [24]. Studies have also highlighted possible links between AQP4 and infectious and neuroinflammatory diseases, most notably meningitis [25], malaria [26] and neuromyelitis optica (NMO) [27].…”

Section: Introductionmentioning

confidence: 99%

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Pro-Inflammatory Role of AQP4 in Mice Subjected to Intrastriatal Injections of the Parkinsonogenic Toxin MPP+

Prydz

Stahl

Zahl

et al. 2020

Cells

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Aquaporin-4 (AQP4) is critically involved in brain water and volume homeostasis and has been implicated in a wide range of pathological conditions. Notably, evidence has been accrued to suggest that AQP4 plays a proinflammatory role by promoting release of astrocytic cytokines that activate microglia and other astrocytes. Neuroinflammation is a hallmark of Parkinson’s disease (PD), and we have previously shown that astrocytes in substantia nigra (SN) are enriched in AQP4 relative to cortical astrocytes, and that their complement of AQP4 is further increased following treatment with the parkinsonogenic toxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Here, we investigated the effect of Aqp4 deletion on microglial activation in mice subjected to unilateral intrastriatal injection of 1-methyl-4-phenylpyridinium (MPP+, the toxic metabolite of MPTP). Our results show that MPP+ injections lead to a pronounced increase in the expression level of microglial activating genes in the ventral mesencephalon of wild type (WT) mice, but not Aqp4−/− mice. We also show, in WT mice, that MPP+ injections cause an upregulation of nigral AQP4 and swelling of astrocytic endfeet. These findings are consistent with the idea that AQP4 plays a pro-inflammatory role in Parkinson’s disease, secondary to the dysregulation of astrocytic volume homeostasis.

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Section: Discussionsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Pro-Inflammatory Role of AQP4 in Mice Subjected to Intrastriatal Injections of the Parkinsonogenic Toxin MPP+

Prydz

Stahl

Zahl

et al. 2020

Cells

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“…For example, targeting neurotoxic reactive A1 astrocytes may revise the neurodegeneration and repair the function of neurons in HD (22). Additionally, we found that reactive astrocytes impeded the delivery of antisense oligonucleotides (ASOs) to deeper brain structures whereas inhibition of reactive astrocytes could increase the efficacy of ASOs in transgenic HD animals (23). In clinical practice, disease burden calculated by CAP score, an index of cumulative toxicity of mHTT, is used to estimate the proximity to HD diagnosis and reflect the severity of striatal dysfunction (24,25).…”

Section: Discussionmentioning

confidence: 96%

Evaluation of Blood Glial Fibrillary Acidic Protein as a Potential Marker in Huntington's Disease

You

et al. 2021

Front. Neurol.

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Objective: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. Neurofilament light protein (NfL) is correlated with clinical severity of HD but relative data are the lack in the Chinese population. Reactive astrocytes are related to HD pathology, which predicts their potential to be a biomarker in HD progression. Our aim was to discuss the role of blood glial fibrillary acidic protein (GFAP) to evaluate clinical severity in patients with HD.Methods: Fifty-seven HD mutation carriers (15 premanifest HD, preHD, and 42 manifest HD) and 26 healthy controls were recruited. Demographic data and clinical severity assessed with the internationally Unified Huntington's Disease Rating Scale (UHDRS) were retrospectively analyzed. Plasma NfL and GFAP were quantified with an ultra-sensitive single-molecule (Simoa, Norcross, GA, USA) technology. We explored their consistency and their correlation with clinical severity.Results: Compared with healthy controls, plasma NfL (p < 0.0001) and GFAP (p < 0.001) were increased in Chinese HD mutation carriers, and they were linearly correlated with each other (r = 0.612, p < 0.001). They were also significantly correlated with disease burden, Total Motor Score (TMS) and Total Functional Capacity (TFC). The scores of Stroop word reading, symbol digit modalities tests, and short version of the Problem Behaviors Assessments (PBAs) for HD were correlated with plasma NfL but not GFAP. Compared with healthy controls, plasma NfL has been increased since stage 1 but plasma GFAP began to increase statistically in stage 2.Conclusions: Plasma GFAP was correlated with plasma NfL, disease burden, TMS, and TFC in HD mutation carriers. Plasma GFAP may have potential to be a sensitive biomarker for evaluating HD progression.

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“…For example, it has been shown that intrathecal administration of ASOs can reduce HTT levels by 70% in the cortex but only by 35% in the striatum. 54 Likewise, a bolus cisternal injection of ASOs reduces HTT levels by 60% in the cortex and by 36% in the striatum. 54 Another study also revealed that injection of ASOs into the CSF of non-human primates can reduce HTT mRNA levels by 53% in the anterior cortex but only 25% in the striatum.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic reversal of Huntington’s disease by in vivo self-assembled siRNAs

Zhang

Shan

et al. 2021

Brain

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Huntington’s disease is an autosomal-dominant neurodegenerative disease caused by CAG expansion in exon 1 of the huntingtin (HTT) gene. Since mutant huntingtin (mHTT) protein is the root cause of Huntington’s disease, oligonucleotide-based therapeutic approaches using small interfering RNAs (siRNAs) and antisense oligonucleotides designed to specifically silence mHTT may be novel therapeutic strategies for Huntington’s disease. Unfortunately, the lack of an effective in vivo delivery system remains a major obstacle to realizing the full potential of oligonucleotide therapeutics, especially regarding the delivery of oligonucleotides to the cortex and striatum, the most severely affected brain regions in Huntington’s disease. In this study, we present a synthetic biology strategy that integrates the naturally existing exosome-circulating system with artificial genetic circuits for self-assembly and delivery of mHTT-silencing siRNA to the cortex and striatum. We designed a cytomegalovirus promoter-directed genetic circuit encoding both a neuron-targeting rabies virus glycoprotein tag and an mHTT siRNA. After being taken up by mouse livers after intravenous injection, this circuit was able to reprogramme hepatocytes to transcribe and self-assemble mHTT siRNA into rabies virus glycoprotein-tagged exosomes. The mHTT siRNA was further delivered through the exosome-circulating system and guided by a rabies virus glycoprotein tag to the cortex and striatum. Consequently, in three mouse models of Huntington’s disease treated with this circuit, the levels of mHTT protein and toxic aggregates were successfully reduced in the cortex and striatum, therefore ameliorating behavioural deficits and striatal and cortical neuropathologies. Overall, our findings establish a convenient, effective and safe strategy for self-assembly of siRNAs in vivo that may provide a significant therapeutic benefit for Huntington’s disease.

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Mesenchymal stem cells alleviate AQP-4-dependent glymphatic dysfunction and improve brain distribution of antisense oligonucleotides in BACHD mice

Cited by 32 publications

References 44 publications

Pro-Inflammatory Role of AQP4 in Mice Subjected to Intrastriatal Injections of the Parkinsonogenic Toxin MPP+

Pro-Inflammatory Role of AQP4 in Mice Subjected to Intrastriatal Injections of the Parkinsonogenic Toxin MPP+

Evaluation of Blood Glial Fibrillary Acidic Protein as a Potential Marker in Huntington's Disease

Therapeutic reversal of Huntington’s disease by in vivo self-assembled siRNAs

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