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Experimental Neuropathology

Cerebral proteopathy is a unifying term for neurodegenerative diseases in which aggregated proteins are abnormally deposited in the brain. The hallmark proteopathy is Alzheimer’s disease (AD). In AD a key early event is the misfolding and aggregation of the amyloid-β peptide (Aβ). What the initial trigger is for the misfolding and how the aggregation of disease-specific proteins leads to neurodegeneration is largely unknown.

Main objectives
Recent results
Staff
Publications

1. To understand how Aβ aggregation originates, spreads, and leads to neuronal dysfunction and dementia.

2. To study non-Aβ proteopathies in order to determine their similarities and differences relative to the Aβ-type.

To this end, we are using organotypic slice cultures and a variety of genetically engineered mouse models of cerebral β-amyloidoses, tauopathies and α-synucleinopathies. To foster the translational and therapeutic aspects of our work, the results obtained from our mouse models are analyzed in comparison to those in the respective human patient samples. 

One seminal finding from our group was the observation that dilute extracts of Aβ-containing material, either from the brains of AD patients or from aged Aβ precursor protein- (APP) transgenic mice, are able to induce cerebral β-amyloidosis and associated lesions in the brains of young APP-transgenic mice (Meyer-Lühmann et al., Science 2006; Eisele et al., Science 2010). When Aβ is biochemically inactivated or removed from the brain samples, the extracts lose the ability to induce Aβ deposition, showing that Aβ itself is necessary for the amyloid induction. Surprisingly, however, synthetic Aβ is much less efficient in inducing the amyloid lesions, suggesting that the ability of Aβ to induce cerebral β-amyloidosis requires that the Aβ molecules acquire certain structural characteristics or co-factors that are generated in the living brain (Aβ seeds). While the self-propagating nature of Aβ aggregates bears important similarities to that of prions, there is no evidence that AD is transmissible in the same sense as are prion diseases (Jucker and Walker, Nature 2013; Jucker and Walker, Nature Neurosci 2018).

The prion-paradigm, however, implies that the conformational characteristics of Aβ seeds govern the type and toxicity of Aβ deposition. Indeed, we have found evidence that the various clinical features of AD may be the result from different molecular Aβ conformations (Rasmussen et al., PNAS 2017). Moreover, the self-propagating nature of Aβ aggregates raise the possibility that Aβ seeds could serve as very early diagnostic biomarker for cerebral β-amyloidosis and maybe AD. This idea is further supported by our finding that the most potent Aβ seeds are small and soluble and may thus occur in bodily fluids (Langer et al., J Neurosci 2011). 

Similar to Aβ seeds, α-synuclein seeds are not only very active but also durable and resist formaldehyde treatment (Fritschi et al., Acta Neuropathol 2014; Schweighauser et al., Acta Neuropathol 2015). The discovery that Aβ seeds can persist in the brain for months at levels below routine detection indicates that the initial changes that drive AD pathogenesis may occur even earlier than previously thought (Ye et al., Nat Neurosci 2015; Ye et al., EMBO Rep 2017). From a therapeutic standpoint, these findings indicate that the most effective treatments for AD should target the Aβ cascade well before the characteristic deposits of Aβ become detectable by currently available methods (Schelle et al., Ann Neurol 2019). 

Contact: Mathias Jucker  


 
Name
Department
Phone
Email
 Melanie Barth
Melanie Barth PhD Student (DZNE)
Experimental Neuropathology
07071 29-81945 
 Carina Bergmann
Carina Bergmann Master Student
Experimental Neuropathology
07071 29-81951 
 Natalie Beschorner
Natalie Beschorner PhD Student
Experimental Neuropathology
07071 29-81945 
Prof. Dr. Mathias Jucker
Prof. Dr. Mathias Jucker Head of Department
Experimental Neuropathology
07071 29-86863 
 Christine Rother
Christine Rother PhD Student
Experimental Neuropathology
07071 29-81951 
Dr. Alejandro Ruiz Riquelme
Dr. Alejandro Ruiz Riquelme PostDoc (DZNE)
Experimental Neuropathology
07071 29-86853 
Dr. Gaye Tanriöver
Dr. Gaye Tanriöver PostDoc (DZNE)
Experimental Neuropathology
07071 29-87596 
 Ruth Uhlmann
Ruth Uhlmann PhD Student
Experimental Neuropathology
07071 29-81946 

 

Schelle J*, Wegenast-Braun BM*, Fritschi SK, Kaeser SA, Jährling N, Eicke D, Skodras A, Beschorner N, Obermueller U, Häsler LM, Wolfer DP, Mueggler T, Shimshek DR, Neumann U, Dodt H-U, Staufenbiel M, Jucker M (2019) Early Aβ reduction prevents progression of cerebral amyloid angiopathy. Ann Neurology, in press

Jucker M, Walker LC (2018) Propagation and spread of pathogenic protein assemblies in neurodegenerative diseases. Nature neuroscience 21:1341-1349 (Abstract)

Rasmussen J, Krasemann S, Altmeppen H, Schwarz P, Schelle J, Aguzzi A, Glatzel M, Jucker M (2018) Infectious prions do not induce Aβ deposition in an in vivo seeding model. Acta neuropathologica 135:965-967 (Abstract)

Rasmussen J*, Mahler J*, Beschorner N*, Kaeser SA, Häsler LM, Baumann F, Nystrom S, Portelius E, Blennow K, Lashley T, Fox NC, Sepulveda-Falla D, Glatzel M, Oblak AL, Ghetti B, Nilsson KPR, Hammarstrom P, Staufenbiel M, Walker LC, Jucker M (2017) Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer's disease. Proc Natl Acad Sci USA 114: 13018-23 (Abstract)

Ye L*, Rasmussen J*, Kaeser SA, Marzesco AM, Obermuller U, Mahler J, Schelle J, Odenthal J, Kruger C, Fritschi SK, Walker LC, Staufenbiel M, Baumann F, Jucker M (2017) Abeta seeding potency peaks in the early stages of cerebral beta-amyloidosis. Embo Reports 18: 1536-44 (Abstract)

Novotny R*, Langer F*, Mahler J, Skodras A, Vlachos A, Wegenast-Braun BM, Kaeser SA, Neher JJ, Eisele YS, Pietrowski MJ, Nilsson KP, Deller T, Staufenbiel M, Heimrich B, Jucker M (2016) Conversion of Synthetic Aβ to In Vivo Active Seeds and Amyloid Plaque Formation in a Hippocampal Slice Culture Model. J Neurosci 36:5084-93 (Abstract)

Ye L*, Fritschi SK*, Schelle J, Obermüller U, Degenhardt K, Kaeser SA, Eisele YS, Walker LC, Baumann F, Staufenbiel M, Jucker M (2015) Persistence of Aβ seeds in APP null mouse brain. Nat Neurosci 18: 1559-61 (Abstract)

Walker LC, Jucker M (2015) Neurodegenerative diseases: Expanding the prion concept. Annu Rev Neurosci 38:87-103 (Abstract)

Jucker M, Walker LC (2015) Neurodegeneration: Amyloid-β pathology induced in humans. Nature 525:193-4 (Abstract)

Ye L, Hamaguchi T, Fritschi SK, Eisele YS, Obermüller U, Jucker M, Walker LC (2015) Progression of Seed-Induced Aβ Deposition within the Limbic Connectome. Brain Pathol 25:743-52 (Abstract)

Schweighauser M, Bacioglu M, Fritschi SK, Shimshek DR, Kahle PJ, Eisele YS, Jucker M (2014) Formaldehyde-fixed brain tissue from spontaneously ill alpha-synuclein transgenic mice induces fatal alpha-synucleinopathy in transgenic hosts. Acta Neuropathol 129:157-9 (Abstract)

Fritschi SK, Langer F, Kaeser S, Maia LF, Portelius E, Pinotsi D, Kaminski CF, Winkler DT, Maetzler W, Keyvani K, Spitzer P, Wiltfang J, Kaminski Schierle GS, Zetterberg H, Staufenbiel M, Jucker M (2014) Highly potent soluble amyloid-β seeds in human Alzheimer brain but not cerebrospinal fluid. Brain 137:2909-15 (Abstract)

Fritschi SK, Cintron A, Ye L, Mahler J, Bühler A, Baumann F, Neumann M, Nilsson KP, Hammarström P, Walker LC, Jucker M (2014) Aβ seeds resist inactivation by formaldehyde. Acta Neuropathol 128:477-84 (Abstract)

Eisele YS, Fritschi SK, Hamaguchi T, Obermüller U, Füger P, Skodras A, Schäfer C, Odenthal J, Heikenwalder M, Staufenbiel M, Jucker M (2014) Multiple Factors Contribute to the Peripheral Induction of Cerebral β-Amyloidosis. J Neurosci 34:10264-73 (Abstract)

Heilbronner G, Eisele YS, Langer F, Kaeser SA, Novotny R, Nagarathinam A, Aslund A, Hammarström P, Nilsson KP, Jucker M (2013) Seeded strain-like transmission of β-amyloid morphotypes in APP transgenic mice. EMBO Rep 14:1017-22 (Abstract)

Jucker M, Walker LC (2013) Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501:45-51 (Abstract)

Eisenberg D, Jucker M (2012) The amyloid state of proteins in human diseases. Cell 148:1188-203 (Abstract)

Director
Prof. Mathias Jucker mathias.juckeruni-tuebingen.de Address

Center of Neurology
Hertie Institute for Clinical Brain Research
Department Cellular Neurology

Otfried-Müller-Straße 27
D-72076 Tübingen

Phone: +49 (0)7071 29-86863
Fax: +49 (0)7071 29-4521

list of publications