Dataset Information

CSF proteomics of aducanumab treated APP-SAA triple knock-in mice

ABSTRACT: Anti-amyloid β-peptide (Aβ) immunotherapy was developed as treatment for Alzheimer’s disease to reduce and prevent amyloid plaque pathology and its downstream consequences. Efficient amyloid plaque clearance has been proven in clinical trials with Aducanumab, Lecanemab and Donanemab. At least two of these antibodies slow memory decline to some extent and have beneficial effects on daily living activities. The therapeutic effects correlate with the efficacy of plaque 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 therapeutic safety, it is therefore imperative to understand the consequences of anti-Aβ antibody treatment on immune cell function. Here, we investigated the effects of long-term chronic Aducanumab treatment on amyloid plaque pathology and microglial response in the APP-SAA triple knock-in mouse model. Mice were treated weekly with Aducanumab from 4-8 months of age. Long-term treatment with Aducanumab results in a robust and dose-dependent removal of amyloid plaque pathology, with a higher efficiency for removing diffuse over dense-core plaques. Analysis of the CSF proteome indicates a reduction of markers for neurodegeneration including Tau and α-Synuclein, as well as immune cell related proteins.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cerebrospinal Fluid

DISEASE(S): Alzheimer's Disease

SUBMITTER: Stephan Mueller

LAB HEAD: Dr Stefan

PROVIDER: PXD061932 | Pride | 2025-08-25

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	AGCH_2401_CSF_037_Slot1-10_1_11256.d.zip	Other
	AGCH_2401_CSF_038_Slot1-15_1_11270.d.zip	Other
	AGCH_2401_CSF_040_Slot1-35_1_11281.d.zip	Other
	AGCH_2401_CSF_041_Slot1-16_1_11271.d.zip	Other
	AGCH_2401_CSF_042_Slot1-45_1_11291.d.zip	Other

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Publications

Early intervention anti-Aβ immunotherapy attenuates microglial activation without inducing exhaustion at residual plaques.

de Weerd Lis L Hummel Selina S Müller Stephan A SA Paris Iñaki I Sandmann Thomas T Eichholtz Marie M Gröger Robin R Englert Amelie L AL Wagner Stephan S Ha Connie C Davis Sonnet S SS Warkins Valerie V Xia Dan D Nuscher Brigitte B Berghofer Anna A Reich Marvin M Feiten Astrid F AF Schlepckow Kai K Willem Michael M Lichtenthaler Stefan F SF Lewcock Joseph W JW Monroe Kathryn M KM Brendel Matthias M Haass Christian C

Molecular neurodegeneration 20250820 1

Anti-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 impr ...[more]

PMID: 40830489

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Project description:Extracellular senile plaques of amyloid beta (Abeta) are a pathological hallmark in brain of patients with Alzheimer`s Disease (AD). Abeta is generated by the amyloidogenic processing of the amyloid precursor protein (APP). Concomitant to Abeta load, AD brain is characterized by an increase in protein level and activity of the angiotensin-converting enzyme (ACE). ACE inhibitors are a widely used class of drugs with established benefits for patients with cardiovascular disease. However, the role of ACE and ACE inhibition in the development of Abeta plaques and the process of AD-related neurodegeneration is not clear since ACE was reported to degrade Abeta. To investigate the effect of ACE inhibition on AD-related pathomechanisms, we used Tg2576 mice with neuron-specific expression of APPSwe as AD model. From 12 months of age, substantial Abeta plaque load accumulates in the hippocampus of Tg2576 mice as a brain region, which is highly vulnerable to AD-related neurodegeneration. The effect of central ACE inhibition was studied by treatment of 12 month-old Tg2576 mice for six months with the brain penetrating ACE inhibitor captopril. At an age of 18 months, hippocampal gene expression profiling was performed of captopril-treated Tg2576 mice relative to untreated 18 month-old Tg2576 controls with high Abeta plaque load. As an additional control, we used 12 month-old Tg2576 mice with low Abeta plaque load. Whole genome microarray gene expression profiling revealed gene expression changes induced by the brain-penetrating ACE inhibitor captopril, which could reflect the neuro-regenerative potential of central ACE inhibition. Microarray gene expression profiling was performed of hippocampi isolated from aged, 18 month-old Tg2576 (APPSwe-transgenic) AD mice with high Abeta plaque load relative to age-matched Tg2576 mice, which were treated for 6 months with the centrally active ACE inhibitor captopril. Another study group consisted of 12 month-old Tg2576 mice with low Abeta plaque load. In total, three study groups were analyzed, i.e. (i) 18 month-old untreated Tg2576 mice with high Abeta plaque load, (ii) age-matched Tg2576 mice treated for 6 months with the brain-penetrating ACE inhibitor captopril (20 mg/kg body weight/day in drinking water), and (iii) untreated 12 month-old Tg2576 mice with low Abeta plaque load reflecting the time point when captopril treatment was initiated. Two biological replicates were made of each group, and total hippocampal RNA of four mice was pooled for one gene chip.

Project description:Anti-amyloid β-peptide (Aβ) immune therapy was developed as treatment for Alzheimer’s disease (AD) to reduce and prevent amyloid plaque pathology. This approach has proven successful in phase 3 clinical trials of Aducanumab, Lecanemab and Donanemab. These antibodies induce robust amyloid plaque clearance, slow memory decline, and have beneficial effects on daily living activities. The therapeutic effects correlate with the efficacy of plaque removal. Treatment is associated with adverse side-effects, such as oedema and haemorrhages (ARIA-E and -H), which are potentially linked to the induced immune response. To improve therapeutic safety, it is therefore imperative to understand the effects of anti-Aβ antibody treatment on immune cell function. We investigated the effects of long-term chronic Aducanumab treatment on amyloid plaque pathology and microglial response in the APP-SAA triple knock-in mouse model. Mice were treated weekly with Aducanumab from 4-8 months of age. Long-term treatment with Aducanumab results in a robust and dose-dependent removal of amyloid plaque pathology. Analysis of the CSF proteome indicates a reduction of markers for neurodegeneration including tau and α-synuclein. Consistent with a reduction of glucose uptake, the therapeutic effects were accompanied by reduced microglial activation. RNAseq confirmed a dose-dependent decrease in the disease-associated microglia (DAM) transcriptional signature of microglia, which is supported by a parallel decrease of Trem2 protein. However, genes associated with antigen-presentation were still increased after treatment. IHC confirms that Aducanumab treatment increases microglial clustering, as well as MHC-II expression around plaques and ELISA confirmed increased cytokine levels. These findings demonstrate that long-term chronic Aducanumab-mediated removal of Aβ leads to a dose dependent decrease in microglial activation and neurodegeneration, but induces a unique antibody treatment-related microglial phenotype associated with antigen presentation, which may be related to plaques still present after the 4 months treatment period.

Project description:Many studies have sought to circumvent the protective qualities of the blood brain barrier to deliver therapeutic proteins to the brain for the treatment of neurodegenerative diseases. Yet, brain specific uptake, peripheral toxicity, off-target effects, and repeated dosing continue to present considerable challenges. As proof of principle, we sought to determine whether human iPSC-microglia (iMG) could be genetically engineered ex vivo to enable pathology-responsive delivery of amyloid-targeting proteins to the brain. Human iPSCs were CRISPR-edited to express the beta-amyloid degrading enzyme neprilysin (NEP) or secreted neprilysin (sNEP) under control of the endogenous CD9 promoter, a microglial gene that is specifically upregulated in plaque-associated microglia. Following adult-transplantation into xenotolerant, amyloid-accumulating mice (5x-MITRG), beta-amyloid peptides, synaptic markers, and off-target substrate levels were examined. To further determine whether increased engraftment of therapeutic microglia could provide additional disease-modifying efficacy, sNEP iMGs were further modified to confer resistance to CSF1R antagonists, enabling brain-wide engraftment of human microglia. Amyloid pathology and synaptic, inflammatory, and neurodegeneration biomarkers were then assessed. We demonstrate that microglia can be engineered to enable pathology-responsive delivery of therapeutic proteins to the brain. NEP and sNEP xenografted microglia reduced levels of amyloid peptides and oligomers, prevented pathology-associated reductions in synaptic markers, and lowered astrogliosis within the hippocampus and overlying cortex of 5x-MITRG mice without off-target degradation. Surprisingly, sNEP delivery by microglia adjacent to the injection site alone was sufficient to achieve almost all disease-modifying outcomes as effectively as CNS-wide sNEP-microglia engraftment. However, significant reductions in amyloid pathology, dystrophic neurites, and perineuronal nets within the plaque-dense subiculum of 5x-MITRG mice was only achieved following CNS-wide microglial replacement. Taken together, these results demonstrate that human microglia can be engineered as a promising new immune cell therapeutic platform to provide widespread and pathology-responsive delivery of biological therapeutics for the treatment of neurodegenerative disease.