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 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.
1. To understand how Aβ aggregation originates, spreads, and leads to neuronal dysfunction and dementia.
2. To study non-Aβ amyloidoses in order to determine their similarities and differences relative to the Aβ-type.
To this end, we are using 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 amyloid 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; Walker and Jucker, Ann Rev Neurosci 2015).
The prion-paradigm, however, implies that the conformational characteristics of Aβ seeds govern the type (and possibly toxicity) of Aβ deposition and indeed we have found evidence for this (Heilbronner et al., EMBO Rep 2013). The various clinical features of AD may thus be the result from different molecular Aβ conformations. Moreover, the self-propagating nature of Aβ aggregates raise the possibility that Aβ seeds could serve as a 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). 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.
Contact: Mathias Jucker
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)
Dr. Jörg Odenthal
Tel.: +49 (0)7071 29-86862
Fax: +49 (0)7071 29-4757