Prof. Dr. Mathias Jucker
Deputy Speaker and Group Leader
Prof. Jucker is board director at the Hertie Institute for Clinical Brain Research
German Center for Neurodegenerative Diseases (DZNE)
Otfried-Müller-Straße 27
72076 Tübingen
mathias.jucker(at)dzne.de
+49 (0) 7071 / 29-86863
+49 (0) 7071 / 29-4521
More information
Areas of investigation/research focus
Cerebral proteopathy is a unifying term for cerebral neurodegenerative diseases in which aggregated proteins are abnormally deposited in the brain. The hallmark proteopathy is Alzheimer’s disease (AD) in which fibrillar amyloid-β (Aβ) peptide is deposited extracellularly in parenchymal plaques and in the vasculature as cerebral amyloid angiopathy. Our objective is to better understand the cellular and molecular mechanisms of neurodegeneration and the pathogenic proteins that are involved in the development of Alzheimer´s disease and cerebral amyloid angiopathy.
Objectives
1. To understand how Aβ aggregation is initiated, spreads, and leads to neuronal dysfunction and dementia.
2. To study the mechanism of Aβ-CAA and its contribution to dementia.
3. To study non-Aβ amyloidoses with the objective to identify commonalities and differences to the Aβ-type, which in turn provides insight into disease pathomechanisms.
To this end, we have generated a variety of genetically-engineered mouse models of cerebral amyloidosis of the Aβ- and non-Aβ-type. To foster the translational and therapeutic aspect of our work, results obtained from our mouse models are analyzed in comparison to those in the respective human patient samples. Primary neuronal cell cultures are used to study mechanistic approaches.
Recent Results
A hallmark finding from our group is the observation that dilute extracts of Aβ-containing material, from the brains of AD patients or from aged amyloid precursor protein (APP)-transgenic mice, are able to stimulate the induction of β-amyloid deposition and associated lesions in the brains of young APP-transgenic mice. When the Aβ was biochemically inactivated or removed from the brain samples, the extracts lost the ability to induce Aβ-deposition, showing that Aβ itself is necessary for the amyloid induction. Surprisingly, however, synthetic Aβ was unable to induce the amyloid lesions, suggesting that the ability of Aβ to induce cerebral ß-amyloidosis requires that Aβ molecules acquire certain structural characteristics or co-factors that are generated in the living brain. While these findings bear important similarities to that of prion disease, there is currently no evidence that AD is transmissible in the same sense as are prion diseases. However, the findings indicate that cellular or environmental seeds, in addition to genetic factors, could play a critical role in the initiation of AD (Meyer-Lühmann et al., Science 2006; Eisele et al., Science 2010).
A second recent hallmark accomplishment is the generation of a transgenic mouse model of the rare but fatal Familial Danish Dementia (FDD). The cause of FDD is a defect in the BRI2 gene, which results in the misfolding and accumulation of the ADan protein in the brains of FDD patients. The mouse model, almost identical to the FDD patients, exhibits ADan-amyloid around the walls of blood vessels in form of ADan-CAA, microbleeds, neuroinflammation, and ADan-induced tau pathology (neurofibrillary tangles). Fascinatingly, the disease elicited by the ADan lesions is very similar to that of the Aβ-lesions in AD and Aβ-CAA. These findings suggest common disease mechanisms for FDD and AD. Therapies targeting the amyloid structure of the misfolded proteins may be valuable in the treatment for both FDD and AD (Coomaraswamy et al., PNAS 2010) but also other cerebral amyloidoses (Käser et al., Nature Genetics 2007).
Recent Key Publications
Modeling Familial Danish Dementia in mice supports the concept of the amyloid hypothesis of Alzheimer´s disease
Coomaraswamy J, Kilger E, Wölfing H, Schäfer S, Kaeser SA, Wegenast-Braun BM, Hefendehl JK, Wolburg H, Mazzella M, Ghiso J, Goedert M, Akiyama H, Garcia-Sierra F, Wolfer DP, Mathews PM, Jucker M (2010) Proc Natl Acad Sci USA 107:7969-74
Peripherally Applied Aß-Containing Inoculates Induce Cerebral ß-Amyloidosis
Eisele YS, Obermuller U, Heilbronner G, Baumann F, Kaeser SA, Wolburg H, Walker LC, Staufenbiel M, Heikenwalder M, Jucker M (2010) Science 330:980-2
The benefits and limitations of animal models for translational research in neurodegenerative diseases
Jucker M (2010) Nat Med 16:1210-4
Long-term in vivo imaging of β-amyloid plaque appearance and growth in a mouse model of cerebral β-amyloidosis
Hefendehl JK, Wegenast-Braun BM, Liebig C, Eicke D, Milford D, Calhoun ME, Kohsaka S, Eichner M, Jucker M (2011) J Neurosci 31:624-9
Pathogenic protein seeding in Alzheimer´s disease and other neurodegenerative disorder
Jucker M, Walker LC (2011) Ann Neurol, in press
Soluble Ab seeds are potent inducers of cerebral b-amyloid deposition
Langer F, Eisele YS, Fritschi SK, Staufenbiel M, Walker LC, Jucker M (2011) J. Neuroscience, in press