Research Grants
The Foundation supports research projects, scientific publications, events, and other activities focussing on the age-related neurodegenerative diseases. Our efforts are directed to translational approaches based on expertise in biology, biochemistry and biophysics to provide mechanistic, pharmacological and methodological insights for future clinical translation of novel, more specific and effective strategies for diagnosis, prevention and therapy. Because of the presently rather low profits from the Foundation's assets the scientific members of the Board recommend research projects that deserve to be funded. It is currently not possible to submit grant applications.
Funded since 2012
Prof. Dr. Günter Höglinger, Neurologische Klinik und Poliklinik, LMU Klinikum München
Prospective validation of the biological SynNeurGe diagnostic classification criteria for Parkinson’s disease
New: There is growing hope that disease-modifying treatments could target the molecular basis of Parkinson’s disease (PD) even before the onset of symptoms. Therefore, the team proposes a biologically based classification using a three-component system with the following aspects: Presence of pathological alpha-synuclein, evidence of underlying degeneration, and documentation of pathogenic gene variants. The project addresses the need for a comprehensive validation of these criteria in order to finally transfer the research concept into prospectively validated evidence, enabling the objective diagnosis, classification and staging of PD. The research is funded with 85,000 Euro for two years.
Prof. Dr. Michael Sendtner & PD Dr. Michael Briese, Institut für Klinische Neurobiologie, Würzburg
Antisense oligonucleotide-mediated depletion of axonal tau as a therapeutic strategy for treatment of Alzheimer’s disease
Running: While research so far mostly focused on removing senile plaques, it is becoming clear the neurofibrillary tangles (NFTs) might be more closely associated with the pathological mechanisms underlying Alzheimer’s disease (AD). Thus, halting or preventing NFT formation might be a promising therapeutic option. Several approaches have been developed to regulate the involved tau protein in order to prevent the seeding of NFTs. A suitable option might be to selectively block tau production in order to prevent tau aggregation. To further investigate the validity of this strategy, the group will use an AD mouse model and cultured human cortical neurons for testing. The research project will be funded with 50,000 Euro for 18 months.
PD Dr. Till Adhikary, Institut für Molekularbiologie, Universität Marburg
PD Dr. Axel Weber, Institut für Humangenetik, Universität Gießen
Haplotype-specific chromatin interactions and gene regulation at the genomic MAPT locus (chr17q21.31)
Running: The aggregation of the microtubule-associated protein tau (MAPT) in cells of the central nervous system is associated with different kinds of dementia. As the haplotype chr17q21.31 is hereditary, one assumes that it is a key for the development of the so-called tauopathies. The research should provide first basic data on which further studies can be built upon. The research is funded with 39,000 Euro for one year.
Prof. Dr. Dorothee Dormann, Institut für Molekulare Physiologie, Universität Mainz
Analysis of physiological vs. pathological TDP-43 phosphorylation
Running: TDP-43 is a major pathological protein in several neurodegenerative disorders, most notably ALS and Frontotemporal Dementia. Dysfunction of TDP-43 is thought to drive neurodegeneration. The team recently identified C-terminal TDP-43 phosphorylation as potent suppressor of aggregation, raising the question when and how this disease-linked modification is introduced in cells and how it is regulated in health and disease. Too, the team will address the hypothesis that TDP-43 might be preferentially phosphorylated in the phase separated or aggregated state. This research has the potential to uncover so far elusive “physiological” TDP-43 phosphorylation. The research is funded with 110,000 Euro for two years.
Dr. Susanne Wegmann, Deutsches Zentrum für Neurodegenerative Erkrankungen, Charité Berlin
Changes in chromatin architecture induced by Tau protein pathology in Alzheimer’s disease
Running: In Alzheimer’s disease (AD) and tauopathies, the Tau protein accumulates and aggregates in the somatodendritic compartment. Associated with this mislocalization, different disease related changes have been observed in affected neurons. Furthermore, Tau accumulation can impair the transport of proteins and RNA in and out of the nucleus. These findings motivate the team to investigate the effect of pathological Tau missorting and aggregation on the 3D-architecture of neuronal chromatin. The team will explore alterations in nuclear shape and chromatin architecture and the re-arrangement of chromosomal territories in Tau transgenic mice and in human postmortem AD brain. The findings will clarify if chromatin architecture contributes to Tau-induced neurotoxicity and disease pathology in AD. The project is funded with 78,500 Euro for two years.
Prof. Dr. Anja Schneider, Deutsches Zentrum für neurodegenerative Erkrankungen, Bonn
Protein misfolding cyclic amplification (PMCA) analysis of plasma and CSF exosomal alpha-synuclein for the diagnosis of Parkinson’s disease and Lewy Body dementia
Running: The team studies exosomes (extracellular vesicles) in neurodegenerative diseases. Of particular interest is the release of toxic, aggregated proteins such as alpha-synuclein and their contribution to toxicity and the spread of disease pathology in the brain. The aim is to use an assay (PMCA) to quantify the potential of exosomal alpha-synuclein from cerebrospinal fluid (CSF) and plasma, to induce the aggregation of alpha-synuclein and to investigate whether this assay can be used as a diagnostic biomarker in Parkinson's disease. This could also enable diagnosis and prognosis in the prodromal and preclinical stage. The research project is funded with 79,800 Euro for two years.
PD Dr. Chi Wang Ip, Neurology, Universitätsklinikum Würzburg
Translational multiomics for a pathophysiological investigation of dystonia: The role of gene-environment interaction in DYT1, DYT6 and DYT25
Running: Dystonia refers to a group of movement disorders that involve involuntary, prolonged tensions in the muscles. These disorders can occur due to various causes, including neurodegenerative diseases such as Parkinson’s disease or Huntington’s disease. The aim is to carry out a systematic investigation of the relationship between gene and environmental factors and the development of dystonia in three genetically determined monogenic forms, DYT1, DYT6 and DYT25, using multiomics analyses from different tissues. The German DFG is funding the project over the next three years as part of a European Joint Program on Rare Diseases. In addition, the Foundation supports the sequencing and necessary consumables with 60,000 Euro.
Publications: Knorr S et al. (2021) Multifactorial Assessment of Motor Behavior in Rats after Unilateral Sciatic Nerve Crush Injury. J Vis Exp (173). doi: 10.3791/62606 - Rauschenberger L et al. (2021) Second hit hypothesis in dystonia: Dysfunctional cross talk between neuroplasticity and environment. Neurobiol Dis (159). doi: 10.1016/j.nbd.2021. 10551 - Knorr S et al. (2022) Experimental deep brain stimulation in rodent models of movement disorders. Exp Neurol (348). doi: 10.1016/j.exneurol.2021.113926 - Karikari A et al. (2022) Neurodegeneration by alpha-synuclein-specific T cells in AAV-A53T-alpha-synuclein Parkinson’s disease mice. Brain Behav Immun (101). doi: 10.1016/j.bbi. 2022.01.007 - Grotemeyer A et al. (2022) Neuroinflammation in Parkinson’s Disease Putative Pathomechanisms and Targets for Disease-Modification. Front Immunol (13). doi: 10.3389/fimmu.2022.878771 - Rauschenberger L et al. (2022) Age-dependent neurodegeneration and neuroinflammation in a genetic A30P/A53T double-mutated alpha-synuclein mouse model of Parkinson’s disease. Neurobiol Dis (105798). doi: 10.1016/j.nbd. 2022.105798
Prof. Dr. Robert Perneczky, Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität München
Amyloid-beta clearance mechanisms: A multi-modal study on lymphatic, glymphatic and blood-brain-barrier function in Alzheimer’s disease
Finished: The project served to research the complex transport systems of the amyloid beta protein. After initial delays due to the COVID-19 pandemic, the study has now been successfully completed, carrying out valuable additional examinations and including additional study participants with non-Alzheimer neurodegeneration. A total of 82 study participants completed the AD protocol. The largest possible number of these test subjects should be examined after 24 months. The research project was funded with 80,000 Euro.
Publications: Finze A et al. (2023) Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies. Mol Psychiatry. doi: 10.1038/s41380-023-02188-8 § Blennow K et al. (2023) The potential clinical value of plasma biomarkers in Alzheimer’s disease. Alzheimers Dement 19(12):5805-16. doi: 10.1002/alz13455 § Perneczky R et al. (2024) Anti-amyloid antibody treatments for Alzheimer’s disease. Eur J Neurol 31(2):e16049. doi: 10.1111/ene16049 § Perna L et al. (2023) Subjective cognitive complaints and blood biomarkers of neurodegenerative diseases: a longitudinal cohort study. Alzheimers Res Ther 15(1):198. doi: 10.1186/s13195-023-01341-03 § Stockbauer A et al. (2023) Metabolic network alterations as a supportive biomarker in dementia with Lewy bodies with preserved dopamine transmission. Eur J Nucl Med Mol Imaging. doi: 10.1007/s00259-023-06493-w § Sadlon A et al. (2024) Association of Blood MicroRNA Expression and Polymorphisms with Cognitive and Biomarker Changes in Older Adults. J Prev Alzheimers Dis 11(1):230-40. doi: 10.14283/jpad.2023.99 § Biechele G et al. (2024) Associations between sex, body mass index and the individual microglial response in Alzheimer’s disease. J Neuroinflammation 21(1):30. doi: 10.1186/s12974-024-03020-y
Prof. Dr. Susanne A. Schneider, Neurology, Ludwig-Maximilians-Universität München
Heterozygous mutations of Niemann-Pick type C predispose to late-onset neurodegeneration – a clinical, radiological and molecular characterization
Finished: The project was dedicated to the study of mutations in a rare genetic condition called Niemann Pick type C (NPC). Because NPC-family history studies suggest a high proportion of late-onset neurodegenerative diseases. Aim was therefore to systematically assess NPC mutation carriers for signs of neurodegeneration. Findings confirm the hypothesis: The studies carried out support the connection between certain genes and and the development of neurodegenerative disease, and the results are highly relevant. The research project was funded with 93,300 Euro for two years.
Publications: Schneider SA et al. (2019) Do heterozygous mutations of Niemann-Pick type C predispose to late-onset neurodegeneration: a review of the literature. J Neurol 268(6):2055-2064. doi: 10.1007/s00415-019-09621-5 ▪ Havla J et al. (2020) Retinal axonal degeneration in Niemann-Pick type C diseases. J Neurol 267(7):2070-2082. doi: 10.1007/s00415-020-09796-2 ▪ Bremova-Ertl T et al. (2020) Clinical, ocular motor, and imaging profile of Niemann-Pick type C heterozygosity. Neurology 94(16):e1702-e1715. doi: 10.1212/WNL.0000000000009290 ▪ Schneider SA & Alcalay RN (2020) Precision medicine in Parkinson’s disease: emerging treatments for genetic Parkinson’s disease. J Neurol 267(3):860-869, doi: 10.1007/s00415-020-09705-7 ▪ Schneider SA et al. (2020) Emerging targeted therapeutics for genetic subtypes of Parkinsonism. Neurotherapeutics 17(4):1378-1392. doi: 10.1007/s13311-020-00920-8 ▪ Colombo A et al. (2021) Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia. Nat Commun 12(1):1158. doi: 10.1038/s41467-021-21428-5 ▪ Bremova-Ertl T et al. (2021) Efficacy and safety of N-acetyl-L-leucine in Niemann-Pick disease type C. J Neurol 1-12. doi: 10.1007/s00415-021-10717-0 ▪ Majovska J et al. (2021) Pontocerebellar atrophy is the hallmark neuroradiological finding in late-onset Tay-Sachs disease (submitted)
Prof. Dr. Alexandra Dürr, Institut du Cerveau et de la Moelle Epinière, Paris
Identification of genetic, epigenetic and environmental modifiers in hereditary spastic paraplegia
Finished: Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder with genetic modulators. Aim was to contribute to the further identification of genetic, epigenetic and/or environmental influences that can predict onset, progression and outcome and, thus, lead to the development of new treatments. Comparison of missense and truncating gene mutations revealed a significantly lower age at onset for patients carrying missense mutations. Too, the cohort of patients allowed to identify a significantly younger age at onset in missense mutations carriers and lower penetrance in females, despite more severe disorder. The findings might lead to novel approaches for treatment. The extensive study has been funded with 309,000 Euro for six years.
Publications: Elsayed LE et al. (2016) Hereditary spastic paraplegias: Identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan. Eur J Hum Genet 25(1):100-10. doi: 10.1038/ejhg.2016.108 ▪ Parodi L et al. (2017) Hereditary spastic paraplegia: More than an upper motor neuron diesease. Rev Neurol 173(5):352-60. doi: 10.1016/j.neurol.2017.03.034 ▪ Parodi L et al. (2018) Spastic paraplegia due to SPAST mutations is modified by the underlying mutation and sex. Brain 141(12):3331-42. doi: 10.1093/brain/awy285 ▪ Coarelli G. et al. (2019) Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7. Neurology 92(23):e2670-90. doi: 10.1212/WNL.0000000000007606 ▪ Huin V et al. (2020) Homo-zygous GRN mutations: unexpected phenotypes and new insights into pathological and molecular mechanisms. Brain 143(1):303-10. doi: 10.1093/brain/awz377 ▪ Méreaux JL et al. (2021) Increasing involvement of CAPN1 variants in spatic ataxias and phenotype-genotype correlations. Neurogenetics 22:71-9. doi: 20.2007/s10048-020-00633-2 ▪ Lallemant-Dudek P & Dürr A (2021) Clinical and genetic update of hereditary spastic paraparesis. Rev Neurol 177(5):550-6. doi: 10.1016/j.neurol.2020.07.001 ▪ Parodi L et al. (2022) The mitochondrial seryl-tRNA synthetase SARS2 modifies onset in spastic paraplegia type 4 (submitted)
Prof. Dr. Dominik Paquet, Institute for Stroke and Dementia Research, Ludwig-Maximilians-Universität München
Elucidating the role of Tau isoform expression in human iPSC-derived Tauopathy models
Finished: The study was to induce latestage disease hallmarks in human stem-cell derived Tauopathy models by mimicking the composition of TAU protein and its environment in an adult human brain. These advanced stem-cell-based human brain tissue models shall become an important resource to study human-specific aspects of brain function and dysfunction, contribute to a better understanding of the molecular disease mechanisms underlying Tauopathies, and provide a new basis for drug development. A CRISPR/Cas9 technology has been developed and successfully applied, cultures of cell lines have been established, assays for phenotypic characterization are now available and immunocytochemistry experiments have started. Preliminary data led to an iAward of the Sanofi Innovation Award Program 2020.The research project was funded with 80,000 € for two years.
Publications: Klimmt J, Dannert A, Paquet D (2020) Neurodegeneration in a dish: advancing human stem-cell-based models of Alzheimer’s disease. Curr Opin Neurobiol 61:96-104. doi: 10.1016/j.conb.2020.01.008 ▪ Weisheit I, Kroeger JA, Malik R, Klimmt J, Crusius D, Dannert A, Dichgans M, Paquet D (2020) Detection of deleterious on-target effects after HDR-mediated CRISPR editing. Cell Rep. 31(8):107689. doi: 10.1016/j.celrep.2020.107689
Dr. Frits Kamp, Biochemistry, Ludwig-Maximilians-Universität, München
Identification of putative gamma-secretase associated steroids and their modulating effects on APP substrate cleavage
Finished: Aims were the identification of high-affinity lipid-binding sites in gamma-secretase and the modulation of gamma-secretase mediated C99-TMD substrate cleavage by neurosteroids. Study design and methods were supposed to deliver new important information about the structure and function of gamma-secretase in order to explain which role lipid changes play in the progression of Alzheimer’s disease. There is now consolidated evidence that both gamma-secretase and its C99 substrate have a cholesterol-binding site. New techniques were established to detect binding of steroids to C99, and certain neurosteroids were found that might dramatically modulate C99 processing by gamma-secretase. Further tests will be carried out. The research project was funded with 60,000 € for two years.
Publications: Kamp F et al. (2018) Bexarotene Binds to the Amyloid Precursor Protein Transmembrane Domain, Alters Its alpha-Helical Conformation, and Inhibits gamma-Secretase Nonselectivity in Liposomes. ACS Chem Neurosci 9(7):1702-13. doi:10.1021/acschemneuro.8b00068 - Junker J et al. (2019) Comparison of Strategies for the Determination of Sterol Sulfates via GC-MS Leading to a Novel Deconjugation-Derivatization Protocol. Molecules 24(13):pii: E2353. doi: 10.3390/molecules24132353 - Götz A et al. (2019) Modulating Hinge Flexibility in the APP Transmembrane Domain Alters gamma-Secretase Cleavage. Biophys J 116(11):2103-20. doi: 10.1016/bpj.2019.04.030
Dr. Johannes Levin, Ludwig-Maximilians-Universität, München
Establishment of a cohort of patients with Down syndrome (Trisomy 21) for imaging and biomarker studies
Finished: Approximately three out of four patients with Down syndrome develop a dementia from the fifth decade of live onwards. The anatomical distribution of pathological alterations are similar to the ones of patients with Alzheimer disease. Aims of the study are to recruit a cohort of patients with Down syndrome, to clinically evaluate them, to determine if these patients show different cerebrospinal fluid and plasma concentations of the soluble protein TREM2, and to test how these differences are associated. After a short delay in recruiting patients progress has been made, a new ambulance has been established and patients care has been further standardized using specialized neuropsychological testing procedures. Yet, building a cohort of patients with Down syndrome was not successful. Part of the study was funded with 65,000 €.
Prof. Dr. Robert Perneczky, Klinik für Psychiatrie und Psychotherapie, Ludwig-Maximilians-Universität München
1st International Conference on Brain and Cognitive Reserve in Dementia Disorders
Finished: The high calibre two-day conference at the University of Munich in November 2017 focussed mainly on investigations of the structural and the functional brain mechanismens, which can delay or even prevent dementia onset. Too, research on neuroimaging and biomarkers have been addressed. The aim of the international conference (1) a gain in knowledge and (2) a better network of the leading scientists in this area of research has been achieved. Funding by the Foundation was 40,000 €.
Publication: Perneczky R et al. (2019) Translational research on reserve against neurodegenerative disease: concensus report of the International Conference on Cognitive Reserve in the Dementias and Alzheimer's Association Reserve, Resilience and Protective Factors Professional Interest Area working groups. BMC Medicine 17:47. doi: 10.1186/s12916-019-1283-z
Prof. Sascha Weggen, Institut für Neuropathologie, Heinrich-Heine-Universität Düsseldorf
A novel metalloprotease in Abeta peptide generation and Alzheimer's disease
Finished: The effects of ADAMTS4, a metalloprotease, on Abeta generation in primary neurons and in transgenic Alzheimer mouse models are characterized. Aims are to confirm these effects, to investigate a direct interaction between ADAMTS4 and APP (Amyloid Precursor Protein), to compare mRNA and protein expression levels of ADAMTS4 in brain samples from Alzheimer patients and non-demented controls, and to investigate the physiological relevance of ADAMTS4 for brain Abeta levels in vivo. The successful research work offers important insights into the processing of amylodogenic fragments of the APP protein. The study was funded with 81,450 € for 2 years.
Publikationen: Bradshaw NJ et al. (2017) Disrupted in Schizophrenia 1 regulates the procession of reelin in the perinatal cortex. Schizophr Res: S0920-9964(17)30200-1. doi: 10.1016/j.schres.2017.04.12 ▪ Wirths O et al. (2017) N-truncated Abeta4-x peptides in sporadic Alzheimer's disease cases and transgenic Alzheimer mouse models. Alzheimers Res Ther 9(1):80. doi: 10.1186/s13195-017-0309-z ▪ Walter S et al. (2018) The metalloprotease ADAMTS4 generates N-truncated Abeta4-x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer's disease. Acta Neuropathol [Epub ahead of print] doi: 10.1007/s00401-018-1929-5
Prof. Alexis Brice, Association pour le Développement de la Recherche sur les Maladies Génétiques, Neurologiques et Psychiatriques, Paris
Use of next generation sequencing to improve knowledge of the molecularer bases of spinocerebellar degenerations
Finished: Based on preliminary work the knowledge of the molecular bases of spinocerebellar degenerations was to be improved. The group could - partly in an international cooperation - identify multiple genes, increase the knowledge of the molecular bases of the described diseases by the extension of the phenotype and inheritance modes of known genes and highlight the functional link between lysosomal storage and frequent forms of autosomal recessive spastic paraplegia, thus, opening avenues of research to therapeutic intervention. The study was funded with 129 000 € for two years.
Publications: Novarino G et al. (2014) Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 343(6170):506-11. doi: 10.1126/science.1247363. ▪ Esteves T et al. (2014) Loss of association of REEP2 with membranes leads to hereditary spastic paraplegia. Am J Hum Genet 92(2):268-77. doi: 10.1016/j.ajhg.2013.12.005. ▪ Di Gregorio E et al. (2014) ELOV5 mutations cause spinocerebellar ataxia 38. Am J HUM Genet 92(2):209-17. doi: 10.1016/j.ajhg.2014.07.001 ▪ Coutelier M et al. (2015) GRID2 mutations span from congenital to mild adult-onset cerebellar ataxia. Neurology 84(17):1751-9. doi: 10.1212/WNL.0000000000001524. ▪ Coutelier M et al. (2015) Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic. Brain 138(Pt 8):2191-205. doi: 10.1093/brain/awv143. ▪ Hirst J et al. 2015) Loss of AP-5 results in accumulation of aberrant endolysosomes: defining a new type of lysosomal storage disease. Hum Mol Genet 24(17):4984-96. doi: 10.1093/hmg/ddv220. ▪ Coutelier M et al. (2015) A recurrent mutation in CACNA1G alters Cav3.1. T-type calcium-channel conduction and causes autosomal-dominant cerebellar ataxia. Am J Hum Genet 97(5):726-37. doi: 10.1016/j.ajhg.2015.09.007 ▪ Elsayed LE et al. (2015) A novel nonsense mutation in DNAJC6 expands the phenotype of autosomal recessive juvenile-onset Parkinson disease. Ann Neurol [Epub ahead of print] doi: 10.1002/ana.24591.
Prof. Paul Saftig, Biochemisches Institut, Christian-Albrechts-Universität zu Kiel, together with
Prof. Stefan Lichtenthaler, Lehrstuhl für Neuroproteomik, Technische Universität München
Therapeutic potential of the Alzheimer alpha-secretase ADAM10
Finished: It has been shown which of the already identified ADAM10 substrate hits are true substrates, which of them undergo increased proteolytic cleavage upon activation of ADAM10, and which of the substrates contribute to the phenotypic changes observed in brains with altered ADAM10 activity. The mouse model was especially helpful and successful. The experimental procedure sets a standard and can now be applied to other substrates in order to determine their potential contribution to the pathogenesis of Alzheimer's disease. The study was funded with 20 000 €.
Papers: Saftig P, Lichtenthaler SF (2015) The alpha secretase ADAM10: A metalloprotease with multiple functions in the brain. Prog. Neurobiol 135:1-20. doi: 10.1016/j.pneurobio.2015.10.003 ▪ Damme M et al. (2014) Autophagy in neuronal cells: general principles and pathological functions. Acta Neuropathol 129(3):337-62. doi: 10.1007/s00401-014-1361-4.
Prof. Paul Saftig, Biochemisches Institut, Christian-Albrechts-Universität zu Kiel together with
Prof. Gerd Multhaup, Pharmacology & Therapeutics Faculty, McGill University, Montreal
Tetraspanins in Alzheimer‘s disease
Finished: It has been shown that tetraspanin encoding genes, especially TSPAN15 and TSPAN3, are susceptible to transcriptional regulation mediated by nuclear Abeta, how far the expression levels of tetraspanins affect APP (Amyloid Precursor Protein) processing and Abeta generation, how tetraspanins affect intracellular APP transport and interaction with other proteins and secretases, and how tetraspanin-expression does affect APP metabolism in vivo. For the experiments transgenic TSPAN mice havebeen generated. The results show a conceptual progress, among others, for the identification of novel biomarkers. The study was funded with 15 000 €.