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.; Nedergaard, Maiken

doi:10.1172/jci.insight.126138

Cited by 30 publications

(20 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To evaluate the entry pathways of CSF to the brain we infused Alexa 647-conjugated bovine serum albumin (BSA) and a Texas Red 3 kDa dextran into the cisterna magna of anesthetized WT and Aqp4 KO mice. In vivo transcranial optical imaging (Plog et al, 2018) of the far-red BSA-647 showed more CSF influx in the WT compared to the KO (Figure 5a and b). Tracer evidently entered the brain parenchyma through a network of perivascular spaces of the large cerebral arteries on the pial surface.…”

Section: Resultsmentioning

confidence: 99%

“…The meta-analysis identified the anesthesia protocol, wide age range of the experimental animals and the injection paradigm are potential causes for the conflicting data reported by Smith et al However, it is important to note that glymphatic transport is affected by multiple pathways other than AQP4. For example, the sleep-wake cycle (Xie et al, 2013), brain injury in the setting of trauma or ischemia (Iliff et al, 2014; Wang et al, 2017), exercise (He et al, 2017; von Holstein-Rathlou et al, 2018; Yin et al, 2018), amyloid-β accumulation and acute amyloid-β toxicity (Xu et al, 2015; Peng et al, 2016), omega-3 fatty acids (Ren et al, 2017), plasma osmolarity (Plog et al, 2018), and aging (Kress et al, 2014) are important regulators of glymphatic transport. How AQP4 on a cellular level facilitates CSF-ISF exchange remains to be firmly established.…”

Section: Discussionmentioning

confidence: 99%

“…Transcranial optical imaging was performed in KX-anesthetized mice as recently described (Plog et al, 2018). To prepare the mouse, the skin overlying the dorsal convexity was reflected and afterwards the cisterna magna was cannulated as described above.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Aquaporin-4-dependent glymphatic solute transport in the rodent brain

Mestre

Hablitz

Xavier

et al. 2018

eLife

Self Cite

444

437

View full text Add to dashboard Cite

The glymphatic system is a brain-wide clearance pathway; its impairment contributes to the accumulation of amyloid-β. Influx of cerebrospinal fluid (CSF) depends upon the expression and perivascular localization of the astroglial water channel aquaporin-4 (AQP4). Prompted by a recent failure to find an effect of Aqp4 knock-out (KO) on CSF and interstitial fluid (ISF) tracer transport, five groups re-examined the importance of AQP4 in glymphatic transport. We concur that CSF influx is higher in wild-type mice than in four different Aqp4 KO lines and in one line that lacks perivascular AQP4 (Snta1 KO). Meta-analysis of all studies demonstrated a significant decrease in tracer transport in KO mice and rats compared to controls. Meta-regression indicated that anesthesia, age, and tracer delivery explain the opposing results. We also report that intrastriatal injections suppress glymphatic function. This validates the role of AQP4 and shows that glymphatic studies must avoid the use of invasive procedures.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Aquaporin-4-dependent glymphatic solute transport in the rodent brain

Mestre

Hablitz

Xavier

et al. 2018

eLife

Self Cite

444

437

View full text Add to dashboard Cite

show abstract

“…In addition to protein clearance, the glymphatic system can potentially be exploited for drug delivery into deep brain structures. In a mouse model of AD, the glymphatic system was used to enhance the delivery of therapeutic antibodies into deep brain regions . 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.…”

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

View full text Add to dashboard Cite

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.

show abstract

“…Additionally, many of the factors impacting on CSF dynamics in ALS patients, including ageing and hypertension, could potentially affect drug distribution following intrathecal injection. However, studies performed in mice have shown that CSF influx into the brain parenchyma could be improved by administering hypertonic saline or mannitol, which both increase plasma osmolality, or ketamine-xylazine, a modulator of slow-wave activity [150,208]. A more recent study further demonstrated that dexmedetomidine, an α2-adrenergic agonist, which also affects slow-wave oscillations, could enhance brain distribution following intrathecal delivery [104].…”

Section: Glymphatic System and Als Neurotherapeuticsmentioning

confidence: 99%

Defining novel functions for cerebrospinal fluid in ALS pathophysiology

Kwong

Mehta

Chandran

2020

acta neuropathol commun

Self Cite

View full text Add to dashboard Cite

Despite the considerable progress made towards understanding ALS pathophysiology, several key features of ALS remain unexplained, from its aetiology to its epidemiological aspects. The glymphatic system, which has recently been recognised as a major clearance pathway for the brain, has received considerable attention in several neurological conditions, particularly Alzheimer's disease. Its significance in ALS has, however, been little addressed. This perspective article therefore aims to assess the possibility of CSF contribution in ALS by considering various lines of evidence, including the abnormal composition of ALS-CSF, its toxicity and the evidence for impaired CSF dynamics in ALS patients. We also describe a potential role for CSF circulation in determining disease spread as well as the importance of CSF dynamics in ALS neurotherapeutics. We propose that a CSF model could potentially offer additional avenues to explore currently unexplained features of ALS, ultimately leading to new treatment options for people with ALS.

show abstract

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

Cited by 30 publications

References 0 publications

Aquaporin-4-dependent glymphatic solute transport in the rodent brain

Aquaporin-4-dependent glymphatic solute transport in the rodent brain

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

Defining novel functions for cerebrospinal fluid in ALS pathophysiology

Contact Info

Product

Resources

About