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34 Publications visible to you, out of a total of 34
The Alzheimer's disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130.

Abstract (Expand)

BACKGROUND: The protease BACE1 is a major drug target for Alzheimer's disease, but chronic BACE1 inhibition is associated with non-progressive cognitive worsening that may be caused by modulation … of unknown physiological BACE1 substrates. METHODS: To identify in vivo-relevant BACE1 substrates, we applied pharmacoproteomics to non-human-primate cerebrospinal fluid (CSF) after acute treatment with BACE inhibitors. RESULTS: Besides SEZ6, the strongest, dose-dependent reduction was observed for the pro-inflammatory cytokine receptor gp130/IL6ST, which we establish as an in vivo BACE1 substrate. Gp130 was also reduced in human CSF from a clinical trial with a BACE inhibitor and in plasma of BACE1-deficient mice. Mechanistically, we demonstrate that BACE1 directly cleaves gp130, thereby attenuating membrane-bound gp130 and increasing soluble gp130 abundance and controlling gp130 function in neuronal IL-6 signaling and neuronal survival upon growth-factor withdrawal. CONCLUSION: BACE1 is a new modulator of gp130 function. The BACE1-cleaved, soluble gp130 may serve as a pharmacodynamic BACE1 activity marker to reduce the occurrence of side effects of chronic BACE1 inhibition in humans.

Authors: S. A. Muller, M. D. Shmueli, X. Feng, J. Tushaus, N. Schumacher, R. Clark, B. E. Smith, A. Chi, S. Rose-John, M. E. Kennedy, S. F. Lichtenthaler

Date Published: 21st Feb 2023

Publication Type: Journal

Beneficial Effect of ACI-24 Vaccination on Abeta Plaque Pathology and Microglial Phenotypes in an Amyloidosis Mouse Model.

Abstract (Expand)

Amyloid-beta (Abeta) deposition is an initiating factor in Alzheimer's disease (AD). Microglia are the brain immune cells that surround and phagocytose Abeta plaques, but their phagocytic capacity … declines in AD. This is in agreement with studies that associate AD risk loci with genes regulating the phagocytic function of immune cells. Immunotherapies are currently pursued as strategies against AD and there are increased efforts to understand the role of the immune system in ameliorating AD pathology. Here, we evaluated the effect of the Abeta targeting ACI-24 vaccine in reducing AD pathology in an amyloidosis mouse model. ACI-24 vaccination elicited a robust and sustained antibody response in APPPS1 mice with an accompanying reduction of Abeta plaque load, Abeta plaque-associated ApoE and dystrophic neurites as compared to non-vaccinated controls. Furthermore, an increased number of NLRP3-positive plaque-associated microglia was observed following ACI-24 vaccination. In contrast to this local microglial activation at Abeta plaques, we observed a more ramified morphology of Abeta plaque-distant microglia compared to non-vaccinated controls. Accordingly, bulk transcriptomic analysis revealed a trend towards the reduced expression of several disease-associated microglia (DAM) signatures that is in line with the reduced Abeta plaque load triggered by ACI-24 vaccination. Our study demonstrates that administration of the Abeta targeting vaccine ACI-24 reduces AD pathology, suggesting its use as a safe and cost-effective AD therapeutic intervention.

Authors: J. Rudan Njavro, M. Vukicevic, E. Fiorini, L. Dinkel, S. A. Muller, A. Berghofer, C. Bordier, S. Kozlov, A. Halle, K. Buschmann, A. Capell, C. Giudici, M. Willem, R. Feederle, S. F. Lichtenthaler, C. Babolin, P. Montanari, A. Pfeifer, M. Kosco-Vilbois, S. Tahirovic

Date Published: 24th Dec 2022

Publication Type: Journal

Spatial proteomics in three-dimensional intact specimens.

Abstract (Expand)

Spatial molecular profiling of complex tissues is essential to investigate cellular function in physiological and pathological states. However, methods for molecular analysis of large biological specimens … imaged in 3D are lacking. Here, we present DISCO-MS, a technology that combines whole-organ/whole-organism clearing and imaging, deep-learning-based image analysis, robotic tissue extraction, and ultra-high-sensitivity mass spectrometry. DISCO-MS yielded proteome data indistinguishable from uncleared samples in both rodent and human tissues. We used DISCO-MS to investigate microglia activation along axonal tracts after brain injury and characterized early- and late-stage individual amyloid-beta plaques in a mouse model of Alzheimer's disease. DISCO-bot robotic sample extraction enabled us to study the regional heterogeneity of immune cells in intact mouse bodies and aortic plaques in a complete human heart. DISCO-MS enables unbiased proteome analysis of preclinical and clinical tissues after unbiased imaging of entire specimens in 3D, identifying diagnostic and therapeutic opportunities for complex diseases. VIDEO ABSTRACT.

Authors: H. S. Bhatia, A. D. Brunner, F. Ozturk, S. Kapoor, Z. Rong, H. Mai, M. Thielert, M. Ali, R. Al-Maskari, J. C. Paetzold, F. Kofler, M. I. Todorov, M. Molbay, Z. I. Kolabas, M. Negwer, L. Hoeher, H. Steinke, A. Dima, B. Gupta, D. Kaltenecker, O. S. Caliskan, D. Brandt, N. Krahmer, S. Muller, S. F. Lichtenthaler, F. Hellal, I. Bechmann, B. Menze, F. Theis, M. Mann, A. Erturk

Date Published: 22nd Dec 2022

Publication Type: Journal

Experimental evidence for temporal uncoupling of brain Abeta deposition and neurodegenerative sequelae.

Abstract (Expand)

Brain Abeta deposition is a key early event in the pathogenesis of Alzheimer s disease (AD), but the long presymptomatic phase and poor correlation between Abeta deposition and clinical symptoms remain … puzzling. To elucidate the dependency of downstream pathologies on Abeta, we analyzed the trajectories of cerebral Abeta accumulation, Abeta seeding activity, and neurofilament light chain (NfL) in the CSF (a biomarker of neurodegeneration) in Abeta-precursor protein transgenic mice. We find that Abeta deposition increases linearly until it reaches an apparent plateau at a late age, while Abeta seeding activity increases more rapidly and reaches a plateau earlier, coinciding with the onset of a robust increase of CSF NfL. Short-term inhibition of Abeta generation in amyloid-laden mice reduced Abeta deposition and associated glial changes, but failed to reduce Abeta seeding activity, and CSF NfL continued to increase although at a slower pace. When short-term or long-term inhibition of Abeta generation was started at pre-amyloid stages, CSF NfL did not increase despite some Abeta deposition, microglial activation, and robust brain Abeta seeding activity. A dissociation of Abeta load and CSF NfL trajectories was also found in familial AD, consistent with the view that Abeta aggregation is not kinetically coupled to neurotoxicity. Rather, neurodegeneration starts when Abeta seeding activity is saturated and before Abeta deposition reaches critical (half-maximal) levels, a phenomenon reminiscent of the two pathogenic phases in prion disease.

Authors: C. Rother, R. E. Uhlmann, S. A. Muller, J. Schelle, A. Skodras, U. Obermuller, L. M. Hasler, M. Lambert, F. Baumann, Y. Xu, C. Bergmann, G. Salvadori, M. Loos, I. Brzak, D. Shimshek, U. Neumann, L. C. Walker, S. A. Schultz, J. P. Chhatwal, S. A. Kaeser, S. F. Lichtenthaler, M. Staufenbiel, M. Jucker

Date Published: 28th Nov 2022

Publication Type: Journal

Signatures of glial activity can be detected in the CSF proteome.

Abstract (Expand)

Single-cell transcriptomics has revealed specific glial activation states associated with the pathogenesis of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. While these … findings may eventually lead to new therapeutic opportunities, little is known about how these glial responses are reflected by biomarker changes in bodily fluids. Such knowledge, however, appears crucial for patient stratification, as well as monitoring disease progression and treatment responses in clinical trials. Here, we took advantage of well-described mouse models of beta-amyloidosis and alpha-synucleinopathy to explore cerebrospinal fluid (CSF) proteome changes related to their respective proteopathic lesions. Nontargeted liquid chromatography-mass spectrometry revealed that the majority of proteins that undergo age-related changes in CSF of either mouse model were linked to microglia and astrocytes. Specifically, we identified a panel of more than 20 glial-derived proteins that were increased in CSF of aged beta-amyloid precursor protein- and alpha-synuclein-transgenic mice and largely overlap with previously described disease-associated glial genes identified by single-cell transcriptomics. Our results also show that enhanced shedding is responsible for the increase of several of the identified glial CSF proteins as exemplified for TREM2. Notably, the vast majority of these proteins can also be quantified in human CSF and reveal changes in Alzheimer's disease cohorts. The finding that cellular transcriptome changes translate into corresponding changes of CSF proteins is of clinical relevance, supporting efforts to identify fluid biomarkers that reflect the various functional states of glial responses in cerebral proteopathies, such as Alzheimer's and Parkinson's disease.

Authors: T. Eninger, S. A. Muller, M. Bacioglu, M. Schweighauser, M. Lambert, L. F. Maia, J. J. Neher, S. M. Hornfeck, U. Obermuller, G. Kleinberger, C. Haass, P. J. Kahle, M. Staufenbiel, L. Ping, D. M. Duong, A. I. Levey, N. T. Seyfried, S. F. Lichtenthaler, M. Jucker, S. A. Kaeser

Date Published: 14th Jun 2022

Publication Type: Journal

Proteomic profiling in cerebral amyloid angiopathy reveals an overlap with CADASIL highlighting accumulation of HTRA1 and its substrates.

Abstract (Expand)

Cerebral amyloid angiopathy (CAA) is an age-related condition and a major cause of intracerebral hemorrhage and cognitive decline that shows close links with Alzheimer's disease (AD). CAA is … characterized by the aggregation of amyloid-beta (Abeta) peptides and formation of Abeta deposits in the brain vasculature resulting in a disruption of the angioarchitecture. Capillaries are a critical site of Abeta pathology in CAA type 1 and become dysfunctional during disease progression. Here, applying an advanced protocol for the isolation of parenchymal microvessels from post-mortem brain tissue combined with liquid chromatography tandem mass spectrometry (LC-MS/MS), we determined the proteomes of CAA type 1 cases (n = 12) including a patient with hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), and of AD cases without microvascular amyloid pathology (n = 13) in comparison to neurologically healthy controls (n = 12). ELISA measurements revealed microvascular Abeta(1-40) levels to be exclusively enriched in CAA samples (mean: > 3000-fold compared to controls). The proteomic profile of CAA type 1 was characterized by massive enrichment of multiple predominantly secreted proteins and showed significant overlap with the recently reported brain microvascular proteome of patients with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary cerebral small vessel disease (SVD) characterized by the aggregation of the Notch3 extracellular domain. We found this overlap to be largely attributable to the accumulation of high-temperature requirement protein A1 (HTRA1), a serine protease with an established role in the brain vasculature, and several of its substrates. Notably, this signature was not present in AD cases. We further show that HTRA1 co-localizes with Abeta deposits in brain capillaries from CAA type 1 patients indicating a pathologic recruitment process. Together, these findings suggest a central role of HTRA1-dependent protein homeostasis in the CAA microvasculature and a molecular connection between multiple types of brain microvascular disease.

Authors: A. Zellner, S. A. Muller, B. Lindner, N. Beaufort, A. J. M. Rozemuller, T. Arzberger, N. C. Gassen, S. F. Lichtenthaler, B. Kuster, C. Haffner, M. Dichgans

Date Published: 24th Jan 2022

Publication Type: Journal

Proteomic and lipidomic profiling of demyelinating lesions identifies fatty acids as modulators in lesion recovery.

Abstract (Expand)

After demyelinating injury of the central nervous system, resolution of the mounting acute inflammation is crucial for the initiation of a regenerative response. Here, we aim to identify fatty acids … and lipid mediators that govern the balance of inflammatory reactions within demyelinating lesions. Using lipidomics, we identify bioactive lipids in the resolution phase of inflammation with markedly elevated levels of n-3 polyunsaturated fatty acids. Using fat-1 transgenic mice, which convert n-6 fatty acids to n-3 fatty acids, we find that reduction of the n-6/n-3 ratio decreases the phagocytic infiltrate. In addition, we observe accelerated decline of microglia/macrophages and enhanced generation of oligodendrocytes in aged mice when n-3 fatty acids are shuttled to the brain. Thus, n-3 fatty acids enhance lesion recovery and may, therefore, provide the basis for pro-regenerative medicines of demyelinating diseases in the central nervous system.

Authors: H. Penkert, A. Bertrand, V. Tiwari, S. Breimann, S. A. Muller, P. M. Jordan, M. J. Gerl, C. Klose, L. Cantuti-Castelvetri, M. Bosch-Queralt, I. Levental, S. F. Lichtenthaler, O. Werz, M. Simons

Date Published: 26th Oct 2021

Publication Type: Journal

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