Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer’s Disease

Hansen, Henrik H.; Fabricius, Katrine; Barkholt, Pernille; Kongsbak-Wismann, Pernille; Schlumberger, Chantal; Jelsing, Jacob; Terwel, Dick; Termont, Annelies; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

doi:10.1371/journal.pone.0158205

Cited by 42 publications

(22 citation statements)

References 73 publications

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“…We sought to confirm the efficacy of anti‐PD1 treatment in a range of different amyloid‐developing transgenic models used extensively for pharmacological testing in our respective groups (Asberom et al, ; Blanchard et al, ; Deleye et al, ; Games et al, ; Hansen et al, ; Janus et al, ). These strains develop amyloid pathology at different rates and can produce amyloid deposits of significant, compact nature (high thioflavine S reactivity: ThyAPP/PS1 M146L, and ThyAPP/PS1 A246E ) or mostly diffuse deposits (PD‐APP) (Table ).…”

Section: Resultsmentioning

confidence: 99%

Systemic immune‐checkpoint blockade with anti‐PD1 antibodies does not alter cerebral amyloid‐β burden in several amyloid transgenic mouse models

Latta-Mahieu

Elmer²,

Bretteville

et al. 2017

Glia

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Chronic inflammation represents a central component in the pathogenesis of Alzheimer's disease (AD). Recent work suggests that breaking immune tolerance by Programmed cell Death-1 (PD1) checkpoint inhibition produces an IFN-γ-dependent systemic immune response, with infiltration of the brain by peripheral myeloid cells and neuropathological as well as functional improvements even in mice with advanced amyloid pathology (Baruch et al., (): Nature Medicine, 22:135-137). Immune checkpoint inhibition was therefore suggested as potential treatment for neurodegenerative disorders when activation of the immune system is appropriate. Because a xenogeneic rat antibody (mAb) was used in the study, whether the effect was specific to PD1 target engagement was uncertain. In the present study we examined whether PD1 immunotherapy can lower amyloid-β pathology in a range of different amyloid transgenic models performed at three pharmaceutical companies with the exact same anti-PD1 isotype and two mouse chimeric variants. Although PD1 immunotherapy stimulated systemic activation of the peripheral immune system, monocyte-derived macrophage infiltration into the brain was not detected, and progression of brain amyloid pathology was not altered. Similar negative results of the effect of PD1 immunotherapy on amyloid brain pathology were obtained in two additional models in two separate institutions. These results show that inhibition of PD1 checkpoint signaling by itself is not sufficient to reduce amyloid pathology and that additional factors might have contributed to previously published results (Baruch et al., (): Nature Medicine, 22:135-137). Until such factors are elucidated, animal model data do not support further evaluation of PD1 checkpoint inhibition as a therapeutic modality for Alzheimer's disease.

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Section: Resultsmentioning

confidence: 99%

Systemic immune‐checkpoint blockade with anti‐PD1 antibodies does not alter cerebral amyloid‐β burden in several amyloid transgenic mouse models

Latta-Mahieu

Elmer²,

Bretteville

et al. 2017

Glia

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“…In addition, amyloid plaque load was reduced, inflammation was reduced in the cortex, and neurogenesis was enhanced in the dentate gyrus (McClean et al, 2015). On the contrary, other authors did not report beneficial effects of liraglutide on cerebral plaque load, in APP/PS1 transgenic mouse models of AD with two different clinical APP/PS1 mutations (Hansen et al, 2016). In the mouse model, memory deficit was improved by subcutaneous administration of liraglutide (25 nmol/day once daily for 8 week), decreasing the phosphorylation of tau (Qi et al, 2016).…”

Section: Glp-1ras As Neuroprotective Agents In Neurodegenerative Disementioning

confidence: 93%

Glucagon-Like Peptide-1: A Focus on Neurodegenerative Diseases

et al. 2019

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Diabetes mellitus is one of the major risk factors for cognitive dysfunction. The pathogenesis of brain impairment caused by chronic hyperglycemia is complex and includes mitochondrial dysfunction, neuroinflammation, neurotransmitters’ alteration, and vascular disease, which lead to cognitive impairment, neurodegeneration, loss of synaptic plasticity, brain aging, and dementia. Glucagon-like peptide-1 (GLP-1), a gut released hormone, is attracting attention as a possible link between metabolic and brain impairment. Several studies have shown the influence of GPL-1 on neuronal functions such as thermogenesis, blood pressure control, neurogenesis, neurodegeneration, retinal repair, and energy homeostasis. Moreover, modulation of GLP-1 activity can influence amyloid β peptide aggregation in Alzheimer’s disease (AD) and dopamine (DA) levels in Parkinson’s disease (PD). GLP-1 receptor agonists (GLP-1RAs) showed beneficial actions on brain ischemia in animal models, such as the reduction of cerebral infarct area and the improvement of neurological deficit, acting mainly through inhibition of oxidative stress, inflammation, and apoptosis. They might also exert a beneficial effect on the cognitive impairment induced by diabetes or obesity improving learning and memory by modulating synaptic plasticity. Moreover, GLP-1RAs reduced hippocampal neurodegeneration. Besides this, there are growing evidences on neuroprotective effects of these agonists in animal models of neurodegenerative diseases, regardless of diabetes. In PD animal models, GPL-1RAs were able to protect motor activity and dopaminergic neurons whereas in AD models, they seemed to improve nearly all neuropathological features and cognitive functions. Although further clinical studies of GPL-1RAs in humans are needed, they seem to be a promising therapy for diabetes-associated cognitive decline.

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“…Based on that hypothesis, and our previous research in STZ-icv rat model pointing to the altered homeostasis of GLP-1 in plasma in early sAD stage, and capability of oral galactose to improve it (Knezovic et al, 2018), we have hypothesized that transgenic model of fAD might have different response to oral galactose treatment. The preclinical studies of GLP-1 agonists showed mostly positive results in transgenic mice fAD models (Cai et al, 2018;Cao et al, 2018;Chen et al, 2017;Long-Smith et al, 2013;McClean et al, 2015;McClean and Holscher, 2014;McClean and Hölscher, 2014;Tai et al, 2018b) and STZ-icv rat model of sAD (S. Li et al, 2012;Shi et al, 2017;Solmaz et al, 2015), but there are also reports of a possible inefficiency of incretin-based drugs in AD models (Hansen et al, 2016) (Bomba et al, 2013). Therefore, it is necessary to characterize in depth and compare the incretin-related metabolic profile in fAD and sAD animal models.…”

Section: Theorymentioning

confidence: 99%

Cognitive, behavioral and metabolic effects of oral galactose treatment in the transgenic Tg2576 mice

et al. 2019

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Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with insulin resistance and glucose hypometabolism in the brain. Oral administration of galactose, a nutrient that provides an alternative source of energy, prevents and ameliorates early cognitive impairment in a streptozotocin-induced model (STZ-icv) of the sporadic AD (sAD). Here we explored the influence of 2-month oral galactose treatment (200 mg/kg/day) in the familial AD (fAD) by using 5-(5M) and 10-(10M) month-old transgenic Tg2576 mice mimicking the presymptomatic and the mild stage of fAD, and compared it to that observed in 7-month old STZ-icv rats mimicking mild-to-moderate sAD. Cognitive and behavioral performance was tested by Morris Water Maze, Open Field and Elevated Plus Maze tests, and metabolic status by intraperitoneal glucose tolerance test and fluorodeoxyglucose Positron-Emission Tomography scan. The level of insulin, glucagon-like peptide-1 (GLP-1) and soluble amyloid ß1-42 (sAß1-42) was measured by ELISA and the protein expression of insulin receptor (IR), glycogen synthase kinase-3β (GSK-3β), and pre-/post-synaptic markers by Western blot analysis. Although galactose normalized alterations in cerebral glucose metabolism in all Tg2576 mice (5M+2M; 10M+2M) and STZ-icv rats, it did not improve cognitive impairment in either model. Improvement of reduced grooming behavior and normalization in reduced plasma insulin levels were seen only in 5M+2M Tg2576 mice while in 10M+2M Tg2576 mice oral galactose induced metabolic exacerbation at the level of plasma insulin, GLP-1 homeostasis and glucose intolerance, and additionally increased hippocampal sAß1-42 level, decreased IR expression and increased GSK-3β activity. The results indicate that therapeutic potential of oral galactose seems to depend on the stage and the type/model of AD and to differ in the absence and the presence of AD-like pathology.

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Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer’s Disease

Cited by 42 publications

References 73 publications

Systemic immune‐checkpoint blockade with anti‐PD1 antibodies does not alter cerebral amyloid‐β burden in several amyloid transgenic mouse models

Systemic immune‐checkpoint blockade with anti‐PD1 antibodies does not alter cerebral amyloid‐β burden in several amyloid transgenic mouse models

Glucagon-Like Peptide-1: A Focus on Neurodegenerative Diseases

Cognitive, behavioral and metabolic effects of oral galactose treatment in the transgenic Tg2576 mice

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