Interleukin‐12/23 deficiency differentially affects pathology in male and female Alzheimer's disease‐like mice

Eede, Pascale; Obst, Juliane; Benke, Eileen; Yvon‐Durocher, Genevieve; Richard, Bernhard Clemens; Gimber, Niclas; Schmoranzer, Jan; Böddrich, Annett; Wanker, Erich E.; Prokop, Stefan; Heppner, Frank L.

doi:10.15252/embr.201948530

Cited by 25 publications

(20 citation statements)

References 62 publications

(128 reference statements)

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“…We also used only one APP transgenic mouse strain, and this strain lacks a tau pathology which could limit the clinical relevance of our findings. In addition, most of the mice were male, as a result of which we cannot rule out the possibility that there could be differences in the efficacy of treatment in females and this deserves further study as sex differences in APP23 mice pathology have been reported [ 41 ]. Due to the advanced age of the mouse cohort at the end of the treatment period, memory function could not be assessed for a third time.…”

Section: Limitationsmentioning

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

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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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Section: Limitationsmentioning

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

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“…Neuroinflammation is yet another, meanwhile generally accepted, crucial regulator of Aβ pathology 1,5,40 . As neuroinflammation in AD is known to be regulated differentially depending on gender 40 , we examined the neuroinflammatory status of Spermidine-treated male APPPS1 mice. Therefore, the amount of ten cytokines were examined in brain homogenates containing the soluble proteins.…”

Section: Resultsmentioning

confidence: 99%

The autophagy activator Spermidine ameliorates Alzheimer’s disease pathology and neuroinflammation in mice

Freitag

Sterczyk

Schulz

et al. 2020

Preprint

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Deposition of amyloid beta (Aβ) and phosphorylated Tau along with microglia- and astrocyte-mediated neuroinflammation are prominent pathogeneic features of Alzheimer’s Disease (AD). In recent years, impairment of autophagy has also been shown to contribute to AD progression. Here, we provide evidence that oral treatment of amyloid-prone AD-like APPPS1 mice with the autophagy activator Spermidine, a small body-endogenous polyamine often used as dietary supplement, decreased neuroinflammation and reduced neurotoxic soluble Aβ at both early and late stages of AD. Mechanistically, Spermidine induced autophagy in microglia as well as in astrocytes, which subsequently impacted TLR3- and TLR4-mediated inflammatory processes by decreasing cytotoxicity, inflammasome activity and NF-κB signalling. Our data highlight that autophagy targets the inflammatory response of glial cells and emphasize the potential of orally administered autophagy-activating drugs such as Spermidine to interfere with AD progression.

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“…197 Interestingly, the loss of IL-12 and IL-23 signaling through p40 genetic ablation has sex-specific effects in which only males exhibit a reduction in Aβ plaques. 200 The silencing of p40 in aged senescence-accelerated mouse prone-8 (SAMP8) mice also mitigates cognitive decline, Aβ load, and neuronal death. 169 Lastly, ablation of IL-10 in the context of AD is also considered beneficial.…”

Section: F I G U R Ementioning

confidence: 99%

The role of innate immunity in Alzheimer's disease

Ennerfelt

Lukens

2020

Immunological Reviews

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The amyloid hypothesis has dominated Alzheimer's disease (AD) research for almost 30 years. This hypothesis hinges on the predominant clinical role of the amyloid beta (Aβ) peptide in propagating neurofibrillary tangles (NFTs) and eventual cognitive impairment in AD. Recent research in the AD field has identified the brain‐resident macrophages, known as microglia, and their receptors as integral regulators of both the initiation and propagation of inflammation, Aβ accumulation, neuronal loss, and memory decline in AD. Emerging studies have also begun to reveal critical roles for distinct innate immune pathways in AD pathogenesis, which has led to great interest in harnessing the innate immune response as a therapeutic strategy to treat AD. In this review, we will highlight recent advancements in our understanding of innate immunity and inflammation in AD onset and progression. Additionally, there has been mounting evidence suggesting pivotal contributions of environmental factors and lifestyle choices in AD pathogenesis. Therefore, we will also discuss recent findings, suggesting that many of these AD risk factors influence AD progression via modulation of microglia and immune responses.

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Interleukin‐12/23 deficiency differentially affects pathology in male and female Alzheimer's disease‐like mice

Cited by 25 publications

References 62 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

The autophagy activator Spermidine ameliorates Alzheimer’s disease pathology and neuroinflammation in mice

The role of innate immunity in Alzheimer's disease

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