Transcranial optical imaging reveals a pathway for optimizing the delivery of immunotherapeutics to the brain

Plog, Benjamin A.; Mestre, Humberto; Olveda, Genaro E.; Sweeney, Amanda M.; Kenney, H. Mark; Cove, Alexander; Dholakia, Kosha; Tithof, Jeffrey; Nevins, Thomas D.; Lundgaard, Iben; Du, Ting; Kelley, Douglas H.

doi:10.1172/jci.insight.120922

Cited by 74 publications

(83 citation statements)

References 61 publications

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“…Transcranial imaging. Animals were anesthetized with KX at ZT6 or ZT18 and were prepared for transcranial imaging 64,65 . In brief, animals were placed in a stereotaxic frame and the skin was removed from the top of the head to expose the skull.…”

Section: Methodsmentioning

confidence: 99%

Circadian control of brain glymphatic and lymphatic fluid flow

et al. 2020

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The glymphatic system is a network of perivascular spaces that promotes movement of cerebrospinal fluid (CSF) into the brain and clearance of metabolic waste. This fluid transport system is supported by the water channel aquaporin-4 (AQP4) localized to vascular endfeet of astrocytes. The glymphatic system is more effective during sleep, but whether sleep timing promotes glymphatic function remains unknown. We here show glymphatic influx and clearance exhibit endogenous, circadian rhythms peaking during the mid-rest phase of mice. Drainage of CSF from the cisterna magna to the lymph nodes exhibits daily variation opposite to glymphatic influx, suggesting distribution of CSF throughout the animal depends on timeof-day. The perivascular polarization of AQP4 is highest during the rest phase and loss of AQP4 eliminates the day-night difference in both glymphatic influx and drainage to the lymph nodes. We conclude that CSF distribution is under circadian control and that AQP4 supports this rhythm.

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Section: Methodsmentioning

confidence: 99%

Circadian control of brain glymphatic and lymphatic fluid flow

et al. 2020

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“…A recently published study highlights how the glymphatic system may be engaged as a therapeutic pathway. By applying a hypertonic solution, blood flow and perivascular flow could be elevated in wild-type and transgenic APP mice [168]. This points toward a promising therapeutic approach to restore glymphatic system efficiency and avoid Aβ accumulation within the vascular wall and the Virchow-Robin spaces in AD and after stroke.…”

Section: Mendelsohn Andmentioning

confidence: 99%

From Stroke to Dementia: a Comprehensive Review Exposing Tight Interactions Between Stroke and Amyloid-β Formation

Goulay

Romo

Hol

et al. 2019

Transl. Stroke Res.

100

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Stroke and Alzheimer's disease (AD) are cerebral pathologies with high socioeconomic impact that can occur together and mutually interact. Vascular factors predisposing to cerebrovascular disease have also been specifically associated with development of AD, and acute stroke is known to increase the risk to develop dementia. Despite the apparent association, it remains unknown how acute cerebrovascular disease and development of AD are precisely linked and act on each other. It has been suggested that this interaction is strongly related to vascular deposition of amyloid-β (Aβ), i.e., cerebral amyloid angiopathy (CAA). Furthermore, the blood-brain barrier (BBB), perivascular space, and the glymphatic system, the latter proposedly responsible for the drainage of solutes from the brain parenchyma, may represent key pathophysiological pathways linking stroke, Aβ deposition, and dementia. In this review, we propose a hypothetic connection between CAA, stroke, perivascular space integrity, and dementia. Based on relevant pre-clinical research and a few clinical case reports, we speculate that impaired perivascular space integrity, inflammation, hypoxia, and BBB breakdown after stroke can lead to accelerated deposition of Aβ within brain parenchyma and cerebral vessel walls or exacerbation of CAA. The deposition of Aβ in the parenchyma would then be the initiating event leading to synaptic dysfunction, inducing cognitive decline and dementia. Maintaining the clearance of Aβ after stroke could offer a new therapeutic approach to prevent post-stroke cognitive impairment and development into dementia.

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“…In a mouse model of AD, the glymphatic system was used to enhance the delivery of therapeutic antibodies into deep brain regions. 13 Aquaporin-4 (AQP-4), a major component of the glymphatic system, is a water channel protein that is predominantly expressed in the foot processes of astrocytes. The loss of perivascular polarization or genetic deletion of AQP-4 impairs glymphatic function.…”

Section: Introductionmentioning

confidence: 99%

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

Feng

et al. 2019

Stem Cells

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Huntington's disease (HD) is a neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene that results in the production of neurotoxic mutant HTT (mHTT) protein. Suppressing HTT production with antisense oligonucleotides (ASOs) is a promising treatment strategy for HD; however, the difficulty of delivering ASOs to deep brain structures is a major barrier for its clinical application. The glymphatic system of astrocytes involving aquaporin 4 (AQP-4) controls the entry of macromolecules from the cerebrospinal fluid into the brain. Mesenchymal stem cells (MSCs) target astrocytes to inhibit neuroinflammation. Here we examined the glymphatic distribution of ASO in the brain and the therapeutic potential of combining intravenously injection of mesenchymal stem cells (IV-MSC) and ASOs for the treatment of HD. Our results show that Cy3-labeled ASOs entered the brain parenchyma via the perivascular space following cisternal injection, but the brain distribution was significantly lower in AQP-4 −/− as compared with wild-type mice. Downregulation of the AQP-4 M23 isoform was accompanied by decreased brain levels of ASOs in BACHD mice as well as an increase in astrogliosis and phosphorylation of nuclear factor κB (NF-κB) p65. IV-MSC treatment restored AQP-4 M23 expression, attenuated astrogliosis, and decreased NF-κB p65 phosphorylation; it also increased the brain distribution of ASOs and enhanced the suppression of mHTT in BACHD mice.These results suggest that modulating glymphatic activity using IV-MSC is a novel strategy for improving the potency of ASO in the treatment of HD.Teng-teng Wu and Feng-juan Su have contributed equally to this work.

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Transcranial optical imaging reveals a pathway for optimizing the delivery of immunotherapeutics to the brain

Cited by 74 publications

References 61 publications

Circadian control of brain glymphatic and lymphatic fluid flow

Circadian control of brain glymphatic and lymphatic fluid flow

From Stroke to Dementia: a Comprehensive Review Exposing Tight Interactions Between Stroke and Amyloid-β Formation

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

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