scholarly journals 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 ◽  
Vol 13 (1) ◽  
Author(s):  
Gerhard Leinenga ◽  
Wee Kiat Koh ◽  
Jürgen Götz
Keyword(s):  
Combination Therapy ◽  
Spatial Memory ◽  
Combination Treatment ◽  
Amyloid Β ◽  
Plaque Area ◽  
High Cumulative Dose ◽  
Plaque Load ◽  
App23 Mouse ◽  
Brain Antibody ◽  
Total Plaque Area

Abstract 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.

scholarly journals 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 ◽  
Author(s):  
Gerhard Leinenga ◽  
Wee Kiat Koh ◽  
Jürgen Götz
Keyword(s):  
Combination Therapy ◽  
Spatial Memory ◽  
Amyloid Β ◽  
Similar Degree ◽  
Plaque Area ◽  
High Cumulative Dose ◽  
Plaque Load ◽  
App23 Mouse ◽  
Brain Antibody ◽  
Total Plaque Area

AbstractBackgroundAducanumab 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.

scholarly journals 24(S)-Saringosterol Prevents Cognitive Decline in a Mouse Model for Alzheimer’s Disease

Marine Drugs ◽  
2021 ◽  
Vol 19 (4) ◽  
pp. 190
Author(s):  
Nikita Martens ◽  
Melissa Schepers ◽  
Na Zhan ◽  
Frank Leijten ◽  
Gardi Voortman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Cognitive Decline ◽  
Inflammatory Marker ◽  
Amyloid Β ◽  
Liver Fat ◽  
Gas Chromatography Mass Spectrometry ◽  
Memory Decline ◽  
Plaque Load

We recently found that dietary supplementation with the seaweed Sargassum fusiforme, containing the preferential LXRβ-agonist 24(S)-saringosterol, prevented memory decline and reduced amyloid-β (Aβ) deposition in an Alzheimer’s disease (AD) mouse model without inducing hepatic steatosis. Here, we examined the effects of 24(S)-saringosterol as a food additive on cognition and neuropathology in AD mice. Six-month-old male APPswePS1ΔE9 mice and wildtype C57BL/6J littermates received 24(S)-saringosterol (0.5 mg/25 g body weight/day) (APPswePS1ΔE9 n = 20; C57BL/6J n = 19) or vehicle (APPswePS1ΔE9 n = 17; C57BL/6J n = 19) for 10 weeks. Cognition was assessed using object recognition and object location tasks. Sterols were analyzed by gas chromatography/mass spectrometry, Aβ and inflammatory markers by immunohistochemistry, and gene expression by quantitative real-time PCR. Hepatic lipids were quantified after Oil-Red-O staining. Administration of 24(S)-saringosterol prevented cognitive decline in APPswePS1ΔE9 mice without affecting the Aβ plaque load. Moreover, 24(S)-saringosterol prevented the increase in the inflammatory marker Iba1 in the cortex of APPswePS1ΔE9 mice (p < 0.001). Furthermore, 24(S)-saringosterol did not affect the expression of lipid metabolism-related LXR-response genes in the hippocampus nor the hepatic neutral lipid content. Thus, administration of 24(S)-saringosterol prevented cognitive decline in APPswePS1ΔE9 mice independent of effects on Aβ load and without adverse effects on liver fat content. The anti-inflammatory effects of 24(S)-saringosterol may contribute to the prevention of cognitive decline.

scholarly journals Amyloid-β Oligomers Induce Only Mild Changes to Inhibitory Bouton Dynamics

2021 ◽  
Vol 5 (1) ◽  
pp. 153-160 ◽  
Author(s):  
Marvin Ruiter ◽  
Christine Lützkendorf ◽  
Jian Liang ◽  
Corette J. Wierenga
Keyword(s):  
Hippocampal Slices ◽  
Inhibitory Neuron ◽  
Amyloid Β ◽  
Inhibitory Neurons ◽  
Inhibitory Synapses ◽  
Amyloid Β Protein ◽  
Protein Precursor ◽  
Β Protein ◽  
Plaque Load ◽  
Early Alzheimer’S Disease

The amyloid-β protein precursor is highly expressed in a subset of inhibitory neuron in the hippocampus, and inhibitory neurons have been suggested to play an important role in early Alzheimer’s disease plaque load. Here we investigated bouton dynamics in axons of hippocampal interneurons in two independent amyloidosis models. Short-term (24 h) amyloid-β (Aβ)-oligomer application to organotypic hippocampal slices slightly increased inhibitory bouton dynamics, but bouton density and dynamics were unchanged in hippocampus slices of young-adult AppNL - F - G-mice, in which Aβ levels are chronically elevated. These results indicate that loss or defective adaptation of inhibitory synapses are not a major contribution to Aβ-induced hyperexcitability.

scholarly journals In Vitro Synergy and In Vivo Activity of Tigecycline-Ciprofloxacin Combination Therapy against Vibrio vulnificus Sepsis

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Seong Eun Kim ◽  
Hee Kyung Kim ◽  
Su-Mi Choi ◽  
Yohan Yu ◽  
Uh Jin Kim ◽  
...  
Keyword(s):  
Survival Rate ◽  
Mortality Rate ◽  
Combination Therapy ◽  
Combination Treatment ◽  
Vibrio Vulnificus ◽  
Antibiotic Regimen ◽  
Content Type ◽  
Time Kill

ABSTRACT The mortality rate associated with Vibrio vulnificus sepsis remains high. An in vitro time-kill assay revealed synergism between tigecycline and ciprofloxacin. The survival rate was significantly higher in mice treated with tigecycline plus ciprofloxacin than in mice treated with cefotaxime plus minocycline. Thus, combination treatment with tigecycline-ciprofloxacin may be an effective novel antibiotic regimen for V. vulnificus sepsis.

Successful Combination Therapy for Amblyopia Secondary to Micro-Esotropia And Anisometropia

2021 ◽  
pp. 195-200
Keyword(s):  
Visual Acuity ◽  
Combination Therapy ◽  
Refractive Error ◽  
Combination Treatment ◽  
Current Treatment ◽  
Short Term ◽  
Eccentric Fixation ◽  
Case Summary ◽  
Vision Therapy ◽  
Spectacle Correction

Background: Micro-esotropia is a small-angle esodeviation typically less than nine prism diopters. Patients with this ocular condition often develop amblyopia due to the presence of a constant unilateral strabismus and an anisometropic refractive error in the deviated eye. Current treatment methods for strabismic and refractive amblyopia include spectacle correction, patching, and vision therapy (VT). Case Summary: A 9-year-old Asian female presented with a constant left primary micro-esotropia with unsteady eccentric fixation, contributing to mild amblyopia and frequent suppression in the left eye. She also had a hyperopic anisometropic refractive error. Combination treatment of in-office VT with short-term patching therapy (two hours per day) was administered, with the goal of improving her binocularity, fixation, and visual acuity. Conclusions: Amblyopia results from binocular dysfunction, therefore monocular patching therapy alone will not improve the underlying issue. VT is necessary to actively treat binocularity and subsequently improve visual acuity, while short-term patching can be used in combination to effectively target monocular accommodation and fixation.

scholarly journals The Effect of Systemic Methotrexate and Cyclosporine Combination Therapy inPsoriasis Vulgaris Patients in Bandung, Indonesia

2021 ◽  
Vol 33 (3) ◽  
pp. 200
Author(s):  
Oki Suwarsa ◽  
Fatima Aulia Khairani ◽  
Syawalika Ulya Isneny ◽  
Erda Avriyanti ◽  
Hartati Purbo Dharmadji ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Side Effects ◽  
Adverse Effects ◽  
Combination Therapy ◽  
Combination Treatment ◽  
Psoriasis Vulgaris ◽  
Severity Index ◽  
Dermatology Clinic ◽  
Significant Difference ◽  
Pasi Score

Background: Methotrexate (MTX) and cyclosporine have been used as effective systemic mono-therapy for psoriasis. Several factors are considered to switch monotherapy to combination therapy because monotherapy is no longer effective and has higher side effects. Hence,clinicians have avoided systemic therapy combinations due to its toxicity. However, some studies showed that this combination therapy could be usedeffectively for psoriasis patients. Purpose: This study aimed to analyze the efficacy and adverse effects of systemic MTX and cyclosporine combination therapy in Indonesian psoriasis vulgaris patients. Methods: The retrospective study assessed the effectiveness of 3 monthsmono-therapyand combination therapy of systemic MTX and cyclosporine in psoriasisvulgaris patients from 2016–2017 in Dermatology Clinic, Dr. Hasan Sadikin Hospital, Bandung, West Java, Indonesia. Result: Psoriasis area and severity index (PASI) score 90 were achieved in the group MTX (50%) and cyclosporine group (50%), while none in the combination group.However, eight patients (50%) in group MTX and cyclosporine reached the primary endpoint of PASI 50. One patient in cyclosporine group had adverse effects on kidney profiles. Nonetheless, other patients had no biochemical changes. But, there was no significant difference in the change of PASI between each group (p=0.102). Conclusion: We propose that combination therapy of MTX and cyclosporine is relatively safe and efficacious in treating Indonesian psoriasis vulgaris patients. This combination treatment isas effective as MTX or cyclosporinemono-therapy.

Combination therapy with acipimox enhances the effect of growth hormone treatment on linear body growth in the normal and small-for-gestational-age rat

2006 ◽  
Vol 291 (6) ◽  
pp. E1212-E1219 ◽  
Author(s):  
M. H. Vickers ◽  
P. L. Hofman ◽  
P. D. Gluckman ◽  
P. E. Lobie ◽  
W. S. Cutfield
Keyword(s):  
Growth Hormone ◽  
Side Effects ◽  
Combination Therapy ◽  
Gestational Age ◽  
Combination Treatment ◽  
Small For Gestational Age ◽  
Body Growth ◽  
Maternal Undernutrition ◽  
Fasting Plasma ◽  
Linear Body

Growth hormone (GH) therapy is often associated with adverse side effects, including impaired insulin sensitivity. GH treatment of children with idiopathic short stature does not lead to an optimized final adult height. It has been demonstrated that FFA reduction induced by pharmacological antilipolysis can stimulate GH secretion per se in both normal subjects and those with GH deficiency. However, to date, no investigation has been undertaken to establish efficacy of combination treatment with GH and FFA regulators on linear body growth. Using a model of maternal undernutrition in the rat to induce growth-restricted offspring, we investigated the hypothesis that combination treatment with GH and FFA regulators can enhance linear body growth above that of GH alone. At postnatal day 28, male offspring of normally nourished mothers (controls) and offspring born with low birth weight [small for gestational age (SGA)] were treated with saline, GH, or GH (5 mg·kg−1·day−1) in combination with acipimox (GH + acipimox, 20 mg·kg−1·day−1) or fenofibrate (GH + fenofibrate, 30 mg·kg−1·day−1) for 40 days. GH plus acipimox treatment significantly enhanced linear body growth in the control and SGA animals above that of GH, as quantified by tibial and total body length. Treatment with GH significantly increased fasting plasma insulin, insulin-to-glucose ratio, and plasma volumes in control and SGA animals but was not significantly different between saline and GH-plus-acipimox-treated animals. GH-induced lipolysis was blocked by GH plus acipimox treatment in both control and SGA animals, concomitant with a significant reduction in fasting plasma FFA and insulin concentrations. This is the first study to show that GH plus acipimox combination therapy, via pharmacological blocking of lipolysis during GH exposure, can significantly enhance the efficacy of GH in linear growth promotion and ameliorate unwanted metabolic side effects.

scholarly journals EFFECTIVENESS OF PROPOLIS WITH ARTEMISININ COMBINATION THERAPY IN TREATING MICE INFECTED WITH PLASMODIUM BERGHEI

2019 ◽  
pp. 262-264
Author(s):  
NURINDAH SALOKA TRISNANINGRUM ◽  
HENDRI ASTUTY
Keyword(s):  
Body Weight ◽  
Combination Therapy ◽  
Parasite Density ◽  
Combination Treatment ◽  
Plasmodium Berghei ◽  
Artemisinin Combination Therapy ◽  
Inhibitory Effect ◽  
Positive Control ◽  
Negative Control ◽  
Days Of Therapy

Objective: This study aimed to ascertain the effectiveness of combination treatment with propolis and artemisinin-based combination therapy (ACT)in avoiding further resistance to ACT.Methods: A total of 35 mice were injected with Plasmodium berghei and divided into six equal groups: No treatment (negative control), ACT alone(positive control), 75-mg propolis/kg body weight (BW), 150-mg propolis/kg BW, ACT with 75-mg propolis/kg BW, and ACT with 150-mg propolis/kg BW. After 7 days of therapy, parasite density was calculated using a thin blood smear.Results: Parasite density significantly declined after combination treatment with ACT and 150-mg propolis/kg BW.Conclusion: Therapy with propolis alone showed no inhibitory effect on parasites, although its 150-mg/kg-BW dose was effective as an ACT adjuvantmalaria therapy in mice.

scholarly journals Regional differences in Alzheimer’s disease pathology confound behavioural rescue after amyloid-β attenuation

Brain ◽  
2019 ◽  
Vol 143 (1) ◽  
pp. 359-373 ◽  
Author(s):  
Christopher D Morrone ◽  
Paolo Bazzigaluppi ◽  
Tina L Beckett ◽  
Mary E Hill ◽  
Margaret M Koletar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Function ◽  
Spatial Memory ◽  
Regional Differences ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Barnes Maze ◽  
Tau Pathology

Abstract Failure of Alzheimer’s disease clinical trials to improve or stabilize cognition has led to the need for a better understanding of the driving forces behind cognitive decline in the presence of active disease processes. To dissect contributions of individual pathologies to cognitive function, we used the TgF344-AD rat model, which recapitulates the salient hallmarks of Alzheimer’s disease pathology observed in patient populations (amyloid, tau inclusions, frank neuronal loss, and cognitive deficits). scyllo-Inositol treatment attenuated amyloid-β peptide in disease-bearing TgF344-AD rats, which rescued pattern separation in the novel object recognition task and executive function in the reversal learning phase of the Barnes maze. Interestingly, neither activities of daily living in the burrowing task nor spatial memory in the Barnes maze were rescued by attenuating amyloid-β peptide. To understand the pathological correlates leading to behavioural rescue, we examined the neuropathology and in vivo electrophysiological signature of the hippocampus. Amyloid-β peptide attenuation reduced hippocampal tau pathology and rescued adult hippocampal neurogenesis and neuronal function, via improvements in cross-frequency coupling between theta and gamma bands. To investigate mechanisms underlying the persistence of spatial memory deficits, we next examined neuropathology in the entorhinal cortex, a region whose input to the hippocampus is required for spatial memory. Reduction of amyloid-β peptide in the entorhinal cortex had no effect on entorhinal tau pathology or entorhinal-hippocampal neuronal network dysfunction, as measured by an impairment in hippocampal response to entorhinal stimulation. Thus, rescue or not of cognitive function is dependent on regional differences of amyloid-β, tau and neuronal network dysfunction, demonstrating the importance of staging disease in patients prior to enrolment in clinical trials. These results further emphasize the need for combination therapeutic approaches across disease progression.

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