Focused ultrasound delivery of a selective TrkA agonist rescues cholinergic function in a mouse model of Alzheimer’s disease

Xhima, Kristiana; Markham-Coultes, Kelly; Nedev, Hinyu; Heinen, Stefan; Saragovi, H. Uri; Hynynen, Kullervo; Aubert, Isabelle

doi:10.1126/sciadv.aax6646

Cited by 50 publications

(48 citation statements)

References 55 publications

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“…We have also previously shown that the application of SUS achieves BBB opening throughout the brain [17] and, consequently, results in higher brain concentrations of antibodies in an IgG format, with up to 2% of the injected dose reaching the brain as compared to 0.2% without SUS [23]. Studies by us in Tau transgenic mice [22, 23] and work by others [24, 35] have suggested that ultrasound can also be used as an effective drug delivery tool to increase levels on antibodies in the AD brain.…”

Section: Discussionmentioning

confidence: 95%

A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease

Leinenga

Götz

2021

Preprint

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BackgroundAducanumab is an anti-amyloid-β (Aβ) antibody that achieved reduced amyloid pathology in Alzheimer’s disease (AD) trials, but it is controversial whether it also improved cognition. It has been claimed that this would require a sufficiently high cumulative dose of the antibody in the brain. Therapeutic ultrasound, in contrast, has only begun to be investigated in human AD clinical trials. We have previously shown that scanning ultrasound in combination with intravenously injected microbubbles (SUS), that temporarily and safely opens the blood-brain barrier (BBB), removes amyloid and restores cognition in APP23 mice. It has not been directly tested how the effects of SUS compare to immunotherapy or whether a combination therapy is more effective.MethodsIn a study comprising four treatment arms, we tested the efficacy of an Aducanumab analogue, Adu, in comparison to SUS, as well as a combination therapy in APP23 mice, using sham as a control (aged 13-22 months). The active place avoidance (APA) test was used to test spatial memory, and histology and ELISA were used to measure amyloid. Brain antibody levels were also determined.ResultsWe found that both Adu and SUS reduced the total plaque area in the hippocampus to a similar degree, with no additive effect in the combination treatment (SUS+Adu). Whereas there was only a trend towards a reduction for both Adu and SUS in the cortex, the combination trial yielded a statistically significant reduction compared to sham. Only the SUS and SUS+Adu groups included animals that had their plaque load reduced to below 1% from above 10%. There was a robust improvement in spatial memory for SUS+Adu only. In this group, when measured three days post-treatment, Adu levels were still 5-fold increased in the combination therapy compared to delivery of Adu on its own.Together, these findings suggest that SUS should be seriously considered as a treatment option for AD. Alternatively, a combination trial using Aducanumab together with ultrasound to increase brain levels of Aducanumab may be warranted, as the two approaches may engage different (albeit shared) clearance mechanisms.

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Section: Discussionmentioning

confidence: 95%

A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease

Leinenga

Götz

2021

Preprint

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“…We have also previously shown that the application of SUS achieves BBB opening throughout the brain [ 17 ] and, consequently, results in higher brain concentrations of antibodies in an IgG format, with a 19-fold higher concentration of IgG reaching the brain as compared to peripheral injection without SUS [ 23 ]. Studies by us in tau transgenic mice [ 22 , 23 ] and work by others [ 24 , 36 ] have suggested that ultrasound can also be used as an effective drug delivery tool to increase the level of antibodies in the AD brain.…”

Section: Discussionmentioning

confidence: 99%

A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease

2021

View full text Add to dashboard Cite

Background Aducanumab is an anti-amyloid-β (Aβ) antibody that achieved reduced amyloid pathology in Alzheimer’s disease (AD) trials; however, it is controversial whether it also improved cognition, which has been suggested would require a sufficiently high cumulative dose of the antibody in the brain. Therapeutic ultrasound, in contrast, has only begun to be investigated in human AD clinical trials. We have previously shown that scanning ultrasound in combination with intravenously injected microbubbles (SUS), which temporarily and safely opens the blood-brain barrier (BBB), removes amyloid and restores cognition in APP23 mice. However, there has been no direct testing of how the effects of SUS compare to immunotherapy or whether a combination therapy is more effective. Methods In a study comprising four treatment arms, we tested the efficacy of an Aducanumab analog, Adu, both in comparison to SUS, and as a combination therapy, in APP23 mice (aged 13–22 months), using sham as a control. The active place avoidance (APA) test was used to test spatial memory, and histology and ELISA were used to measure amyloid. Brain antibody levels were also determined. Results We found that both Adu and SUS reduced the total plaque area in the hippocampus with no additive effect observed with the combination treatment (SUS + Adu). Whereas in the cortex where there was a trend towards reducing the total plaque area from either Adu or SUS, only the combination treatment yielded a statistically significant decrease in total plaque area compared to sham. Only the SUS and SUS + Adu groups included animals that had their plaque load reduced to below 1% from above 10%. There was a robust improvement in spatial memory for the SUS + Adu group only, and in this group the level of Adu, when measured 3 days post-treatment, was 5-fold higher compared to those mice that received Adu on its own. Together, these findings suggest that SUS should be considered as a treatment option for AD. Alternatively, a combination trial using Aducanumab together with ultrasound to increase brain levels of the antibody may be warranted.

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“…Furthermore, the results of a 2018 clinical trial showed that intranasal administration of NGF could improve cognitive function in two patients with frontotemporal dementia 53 , suggesting a role for NGF in adult human CNS function. The results of these studies [49][50][51][52][53] imply that an intact blood-brain barrier is a prerequisite for the treatment of elderly individuals with NGF inhibitors. Therefore, any patient population with an impaired blood-brain barrier, such as after stroke and in those with multiple sclerosis, Alzheimer disease or neuroinflammatory disorders 54 , should be excluded from treatment with NGF inhibitors.…”

Section: Fig 1 | the Evolution Of Ngf Inhibition In Clinical Medicinementioning

confidence: 99%

“…This effect is transient, reversible and dependent on the stage of postnatal development. NGF might also have a role in Alzheimer disease, as there seems to be a degeneration of cholinergic neurons in the basal forebrain and hippocampus in mice with an experimental model of this disease 52 . Furthermore, the results of a 2018 clinical trial showed that intranasal administration of NGF could improve cognitive function in two patients with frontotemporal dementia 53 , suggesting a role for NGF in adult human CNS function.…”

Section: Fig 1 | the Evolution Of Ngf Inhibition In Clinical Medicinementioning

confidence: 99%

The evolution of nerve growth factor inhibition in clinical medicine

2020

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Focused ultrasound delivery of a selective TrkA agonist rescues cholinergic function in a mouse model of Alzheimer’s disease

Cited by 50 publications

References 55 publications

A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease

A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease

A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease

The evolution of nerve growth factor inhibition in clinical medicine

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