A5043404109- Alzheimer's disease research and treatments
- Amyotrophic Lateral Sclerosis Research
- Parkinson's Disease Mechanisms and Treatments
- Neuroinflammation and Neurodegeneration Mechanisms
- Cellular transport and secretion
- Neurogenetic and Muscular Disorders Research
- Prion Diseases and Protein Misfolding
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Inflammation biomarkers and pathways
- Drug Transport and Resistance Mechanisms
- Cholinesterase and Neurodegenerative Diseases
- Supramolecular Self-Assembly in Materials
- Protein Structure and Dynamics
- Neurological Disease Mechanisms and Treatments
- S100 Proteins and Annexins
- Genomics and Chromatin Dynamics
- Protein Hydrolysis and Bioactive Peptides
- Autophagy in Disease and Therapy
- Computational Drug Discovery Methods
- Cerebrovascular and genetic disorders
- Cell Adhesion Molecules Research
- Endoplasmic Reticulum Stress and Disease
- Neurological diseases and metabolism
- Genetics and Neurodevelopmental Disorders
- Wnt/β-catenin signaling in development and cancer
Ludwig-Maximilians-Universität München
2015-2024
German Center for Neurodegenerative Diseases
2009-2024
Center for Integrated Protein Science Munich
2007
Sine Institute
2004
Brigham and Women's Hospital
1995-2002
Baylor College of Medicine
2002
Indiana University – Purdue University Indianapolis
2002
Indiana University School of Medicine
2002
Heidelberg University
1996-2000
Boehringer Ingelheim (Germany)
2000
TREM2 is a transmembrane receptor that predominantly expressed by microglia in the central nervous system. Rare variants gene increase risk for late-onset Alzheimer's disease (AD). Soluble (sTREM2) resulting from shedding of ectodomain can be detected cerebrospinal fluid (CSF) and surrogate measure TREM2-mediated function. CSF sTREM2 has been previously reported to at different clinical stages AD, however, alterations relation Amyloid β-peptide (Aβ) deposition or additional pathological...
Abstract Loss-of-function variants of TREM2 are associated with increased risk Alzheimer’s disease (AD), suggesting that activation this innate immune receptor may be a useful therapeutic strategy. Here we describe high-affinity human TREM2-activating antibody engineered monovalent transferrin (TfR) binding site, termed transport vehicle (ATV), to facilitate blood–brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced...
To gain insights into the significance of presenilins (PS) in pathogenetic mechanisms early-onset familial Alzheimer disease (FAD), we expressed cDNAs for wild-type PS2 and with Volga German (N141I) mutation cultured cells then examined metabolism transfected proteins their effect on C-terminal properties secreted amyloid β protein (Aβ). was identified as a 50- to 55-kDa protein, which cleaved produce N-terminal fragments 35–40 kDa 19–23 kDa. The did not cause any significant change PS2....
Mutations in the presenilin (PS) genes are linked to early onset familial Alzheimer's disease (FAD). PS-1 proteins proteolytically processed by an unknown protease two stable fragments of ∼30 kDa (N-terminal fragment (NTF)) and ∼20 (C-terminal (CTF)) (Thinakaran, G., Borchelt, D. R., Lee, M. K., Slunt, H. H., Spitzer, L., Kim, Ratovitsky, T., Davenport, F., Nordstedt, C., Seeger, M., Hardy, J., Levey, A. I., Gandy, S. E., Jenkins, N. A., Copeland, Price, Sisodia, (1996) <i>Neuron</i> 17,...
Presenilin-1 (PS1) facilitates γ-secretase cleavage of the β-amyloid precursor protein and intramembraneous Notch1. Although Alzheimer's disease-associated mutations in homologous presenilin (PS2) gene elevate amyloid β-peptide (Aβ42) production like PS1 mutations, here we demonstrate that a ablation PS2 (unlike PS1) mice does not result severe phenotype resembling Notch-ablated animals. To investigate amyloidogenic function more directly, mutagenized conserved aspartate at position 366 to...
Amyloid β-peptide (Aβ) is known to accumulate in senile plaques of Alzheimer's disease (AD) patients and now widely believed play a major role the disease. Two populations peptides occur terminating either at amino acid 40 or 42 (Aβ1–40 Aβ1–42). Alternative N-terminal cleavages produce additional heterogeneity (Aβ<i>x</i>-40 Aβ<i>x</i>-42). Peptides are be player sporadic AD as well familial (FAD). Whereas cellular mechanism for generation Aβ understood, very little about cleavage after 42....
Alzheimer's disease (AD)-associated γ-secretase is a presenilin (PS)- dependent proteolytic activity involved in the intramembraneous cleavage of β-amyloid precursor protein, Notch, LDL receptor-related E-cadherin, and ErbB-4. This cut produces corresponding intracellular domains (ICD), which are required for nuclear signaling Notch probably ErbB-4, protein as well. We have now investigated CD44, cell surface adhesion molecule, also undergoes an to liberate its ICD. demonstrate that this...
β-Secretase (BACE) is a transmembrane aspartyl protease, which generates the N terminus of Alzheimer's disease amyloid β-peptide. Here, we report that BACE can be phosphorylated within its cytoplasmic domain at serine residue 498 by casein kinase 1. Phosphorylation exclusively occurs after full maturation propeptide cleavage and complex N-glycosylation. Phosphorylation/dephosphorylation affects subcellular localization BACE. wild type an S498D mutant mimics are predominantly located...
The Alzheimer's disease (AD)-associated presenilin (PS) proteins are required for the γ-secretase cleavages of β-amyloid precursor protein and site 3 (S3) protease cleavage Notch. These intramembrane release amyloid-β peptide (Aβ), including pathogenic 42-aa variant (Aβ 42 ), as well Notch intracellular domains (AICD, NICD). Whereas Aβ is generated by endoproteolysis in middle transmembrane domain, AICD NICD at analogous positions close to cytoplasmic border domain. Numerous mutations...
Amyloid β-peptide is generated by two sequential proteolytic cleavages mediated β-secretase (BACE) and γ-secretase. BACE was recently identified as a membrane-associated aspartyl protease. We have now analyzed the maturation pro-peptide cleavage of BACE. Pulse-chase experiments revealed that post-translationally modified during transport to cell surface, which can be monitored significant increase in molecular mass. The mass caused complex<i>N</i>-glycosylation. Treatment with tunicamycin...
Numerous mutations causing early onset Alzheimer's disease have been identified in the presenilin (PS) genes, particularly <i>PS1</i> gene. Like within β-amyloid precursor protein gene, PS cause increased generation of a highly neurotoxic variant amyloid β-peptide. proteins are proteolytically processed to an N-terminal ∼30-kDa (NTF) and C-terminal ∼20-kDa fragment (CTF<sub>20</sub>) that form heterodimeric complex. We demonstrate this complex is resistant proteolytic degradation, whereas...
Amyloid beta-peptide (Abeta) is generated by the consecutive cleavages of beta- and gamma-secretase. The intramembraneous gamma-secretase cleavage critically depends on activity presenilins (PS1 PS2). Although there evidence that PSs are aspartyl proteases with activity, it remains controversial whether their subcellular localization overlaps cellular sites Abeta production. We now demonstrate biologically active GFP-tagged PS1 as well endogenous targeted to plasma membrane (PM) living...
Abstract Neuronal and glial deposition of misfolded, proteolytically processed, polyubiquitinated abnormally phosphorylated C‐terminal fragments (CTFs) the TAR DNA binding protein‐43 (TDP‐43) is a pathological hallmark frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD‐U) certain cases amyotrophic lateral sclerosis. We demonstrate that TDP‐43 can be processed by caspases upon induction apoptosis to major 35 kDa minor 25 CTF. These are initially soluble, but over time...
Abstract Immunotherapeutic approaches are currently the most advanced treatments for Alzheimer's disease ( AD ). Antibodies against amyloid β‐peptide (Aβ) bind to plaques and induce their clearance by microglia via Fc receptor‐mediated phagocytosis. Dysfunctions of may play a pivotal role in pathogenesis could result reduced efficacy antibody‐mediated Aβ clearance. Recently, heterozygous mutations triggering receptor expressed on myeloid cells 2 TREM ), microglial gene involved phagocytosis,...
TMEM106B was identified as a major risk factor in genome-wide association study for frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein (TDP)-43 pathology. The most significant of single nucleotide polymorphisms FTLD-TDP observed patients progranulin (GRN) mutations. Subsequent studies suggested an inverse correlation between expression and GRN levels patient serum. However, this study, not confirmed we failed to detect alteration upon knockdown or exogenous heterologous...
Numerous loss-of-function mutations in the progranulin ( GRN ) gene cause frontotemporal lobar degeneration with ubiquitin and TAR–DNA binding protein 43-positive inclusions by reduced production secretion of GRN. Consistent observation that has neurotrophic properties, pharmacological stimulation is a promising approach to rescue haploinsufficiency prevent disease progression. We therefore searched for compounds capable selectively increasing levels. Here, we demonstrate four independent...