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000280744 1001_ $$0P:(DE-2719)9001304$$ade Weerd, Lis$$b0$$eFirst author$$udzne
000280744 245__ $$aEarly intervention anti-Aβ immunotherapy attenuates microglial activation without inducing exhaustion at residual plaques.
000280744 260__ $$aLondon$$bBiomed Central$$c2025
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000280744 520__ $$aAnti-amyloid β-peptide (Aβ) immunotherapy was developed to reduce amyloid plaque pathology and slow cognitive decline during progression of Alzheimer's disease. Efficient amyloid clearance has been proven in clinical trials testing anti-Aβ antibodies, by their impact on cognitive endpoints correlating with the extent of amyloid removal. However, treatment is associated with adverse side effects, such as oedema and haemorrhages, which are potentially linked to the induced immune response. To improve the safety profile of these molecules, it is imperative to understand the consequences of anti-Aβ antibody treatment on immune cell function. Here, we investigated the effects of long-term chronic anti-Aβ treatment on amyloid plaque pathology and microglial response in the APP-SAA triple knock-in mouse model with an intervention paradigm early during amyloidogenesis. Long-term treatment with anti-Aβ results in a robust and dose-dependent lowering of amyloid plaque pathology, with a higher efficiency for reducing diffuse over dense-core plaque deposition. Analysis of the CSF proteome indicates a reduction of markers for neurodegeneration including Tau and α-Synuclein, as well as immune-cell-related proteins. Bulk RNA-seq revealed a dose-dependent attenuation of disease-associated microglial (DAM) and glycolytic gene expression, which is supported by a parallel decrease of glucose uptake and protein levels of Triggering Receptor Expressed on Myeloid cells 2 (Trem2) protein, a major immune receptor involved in DAM activation of microglia. In contrast, DAM activation around residual plaques remains high, regardless of treatment dose. In addition, microglia surrounding residual plaques display a dose-dependent increase in microglial clustering and a selective increase in antigen-presenting and immune signalling proteins. These findings demonstrate that chronic early intervention by an anti-amyloid immunotherapy leads to a dose-dependent decrease in plaque formation, which is associated with lower brain-wide microglial DAM activation and neurodegeneration. Microglia at residual plaques still display a combined DAM and antigen-presenting phenotype that suggests a continued treatment response.
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000280744 650_7 $$2Other$$aAducanumab
000280744 650_7 $$2Other$$aAlzheimer’s disease (AD)
000280744 650_7 $$2Other$$aAmyloid plaque
000280744 650_7 $$2Other$$aImmunotherapy
000280744 650_7 $$2Other$$aMicroglia
000280744 650_7 $$2Other$$aTrem2
000280744 650_7 $$2NLM Chemicals$$aAmyloid beta-Peptides
000280744 650_2 $$2MeSH$$aAnimals
000280744 650_2 $$2MeSH$$aMicroglia: metabolism
000280744 650_2 $$2MeSH$$aMicroglia: drug effects
000280744 650_2 $$2MeSH$$aMicroglia: immunology
000280744 650_2 $$2MeSH$$aMice
000280744 650_2 $$2MeSH$$aPlaque, Amyloid: pathology
000280744 650_2 $$2MeSH$$aPlaque, Amyloid: metabolism
000280744 650_2 $$2MeSH$$aPlaque, Amyloid: immunology
000280744 650_2 $$2MeSH$$aAmyloid beta-Peptides: immunology
000280744 650_2 $$2MeSH$$aAmyloid beta-Peptides: metabolism
000280744 650_2 $$2MeSH$$aAmyloid beta-Peptides: antagonists & inhibitors
000280744 650_2 $$2MeSH$$aImmunotherapy: methods
000280744 650_2 $$2MeSH$$aAlzheimer Disease: pathology
000280744 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000280744 650_2 $$2MeSH$$aAlzheimer Disease: immunology
000280744 650_2 $$2MeSH$$aMice, Transgenic
000280744 650_2 $$2MeSH$$aDisease Models, Animal
000280744 7001_ $$0P:(DE-2719)9002483$$aHummel, Selina$$b1$$udzne
000280744 7001_ $$0P:(DE-2719)2810938$$aMüller, Stephan A$$b2$$udzne
000280744 7001_ $$aParis, Iñaki$$b3
000280744 7001_ $$aSandmann, Thomas$$b4
000280744 7001_ $$aEichholtz, Marie$$b5
000280744 7001_ $$aGröger, Robin$$b6
000280744 7001_ $$aEnglert, Amelie L$$b7
000280744 7001_ $$aWagner, Stephan$$b8
000280744 7001_ $$aHa, Connie$$b9
000280744 7001_ $$aDavis, Sonnet S$$b10
000280744 7001_ $$aWarkins, Valerie$$b11
000280744 7001_ $$aXia, Dan$$b12
000280744 7001_ $$0P:(DE-2719)9000236$$aNuscher, Brigitte$$b13
000280744 7001_ $$0P:(DE-2719)2811640$$aBerghofer, Anna$$b14
000280744 7001_ $$0P:(DE-2719)9001629$$aReich, Marvin$$b15$$udzne
000280744 7001_ $$0P:(DE-2719)9002289$$aFeiten, Astrid Feentje$$b16$$udzne
000280744 7001_ $$0P:(DE-2719)2812546$$aSchlepckow, Kai$$b17$$udzne
000280744 7001_ $$aWillem, Michael$$b18
000280744 7001_ $$0P:(DE-2719)2181459$$aLichtenthaler, Stefan F$$b19$$udzne
000280744 7001_ $$aLewcock, Joseph W$$b20
000280744 7001_ $$aMonroe, Kathryn M$$b21
000280744 7001_ $$0P:(DE-2719)9001539$$aBrendel, Matthias$$b22$$udzne
000280744 7001_ $$0P:(DE-2719)2202037$$aHaass, Christian$$b23$$eLast author$$udzne
000280744 773__ $$0PERI:(DE-600)2244557-2$$a10.1186/s13024-025-00878-1$$gVol. 20, no. 1, p. 92$$n1$$p92$$tMolecular neurodegeneration$$v20$$x1750-1326$$y2025
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