%0 Journal Article %J J Alzheimers Dis %D 2018 %T Comprehensive Characterization of the Pyroglutamate Amyloid-β Induced Motor Neurodegenerative Phenotype of TBA2.1 Mice. %A Dunkelmann, Tina %A Schemmert, Sarah %A Honold, Dominik %A Teichmann, Kerstin %A Butzküven, Elke %A Demuth, Hans-Ulrich %A Shah, Nadim Joni %A Langen, Karl-Josef %A Kutzsche, Janine %A Willbold, Dieter %A Willuweit, Antje %X

Alzheimer's disease (AD) is the most common neurodegenerative disorder and is being intensively investigated using a broad variety of animal models. Many of these models express mutant versions of human amyloid-β protein precursor (AβPP) that are associated with amyloid-β protein (Aβ)-induced early onset familial AD. Most of these models, however, do not develop bold neurodegenerative pathology and the respective phenotypes. Nevertheless, this may well be essential for their suitability to identify therapeutically active compounds that have the potential for a curative or at least disease-modifying therapy in humans. In this study, the new transgenic mouse model TBA2.1 was explored in detail to increase knowledge about the neurodegenerative process induced by the presence of pyroglutamate modified human Aβ3-42 (pEAβ3-42). Analysis of the sensorimotor phenotype, motor coordination, Aβ pathology, neurodegeneration, and gliosis revealed formation and progression of severe pathology and phenotypes including massive neuronal loss in homozygous TBA2.1 mice within a few months. In contrast, the start of a slight phenotype was observed only after 21 months in heterozygous mice. These data highlight the role of pEAβ3-42 in the disease development and progression of AD. Based on the findings of this study, homozygous TBA2.1 mice can be utilized to gain deeper understanding in the underlying mechanisms of pEAβ3-42 and might be suitable as an animal model for treatment studies targeting toxic Aβ species, complementary to the well described transgenic AβPP mouse models.

%B J Alzheimers Dis %V 63 %P 115-130 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29578479?dopt=Abstract %R 10.3233/JAD-170775 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Dipeptidyl-Peptidase Activity of Meprin β Links N-truncation of Aβ with Glutaminyl Cyclase-Catalyzed pGlu-Aβ Formation. %A Schlenzig, Dagmar %A Cynis, Holger %A Hartlage-Rübsamen, Maike %A Zeitschel, Ulrike %A Menge, Katja %A Fothe, Anja %A Ramsbeck, Daniel %A Spahn, Claudia %A Wermann, Michael %A Roßner, Steffen %A Buchholz, Mirko %A Schilling, Stephan %A Demuth, Hans-Ulrich %X

The formation of amyloid-β (Aβ) peptides is causally involved in the development of Alzheimer's disease (AD). A significant proportion of deposited Aβ is N-terminally truncated and modified at the N-terminus by a pGlu-residue (pGlu-Aβ). These forms show enhanced neurotoxicity compared to full-length Aβ. Although the truncation may occur by aminopeptidases after formation of Aβ, recently discovered processing pathways of amyloid-β protein precursor (AβPP) by proteases such as meprin β may also be involved. Here, we assessed a role of meprin β in forming Aβ3-40/42, which is the precursor of pGlu-Aβ3-40/42 generated by glutaminyl cyclase (QC). Similar to QC, meprin β mRNA is significantly upregulated in postmortem brain from AD patients. A histochemical analysis supports the presence of meprin β in neurons and astrocytes in the vicinity of pGlu-Aβ containing deposits. Cleavage of AβPP-derived peptides by meprin β in vitro results in peptides Aβ1-x, Aβ2-x, and Aβ3-x. The formation of N-truncated Aβ by meprin β was also corroborated in cell culture. A subset of the generated peptides was converted into pGlu-Aβ3-40 by an addition of glutaminyl cyclase, supporting the preceding formation of Aβ3-40. Further analysis of the meprin β cleavage revealed a yet unknown dipeptidyl-peptidase-like activity specific for the N-terminus of Aβ1-x. Thus, our data suggest that meprin β contributes to the formation of N-truncated Aβ by endopeptidase and exopeptidase activity to generate the substrate for QC-catalyzed pGlu-Aβ formation.

%B J Alzheimers Dis %V 66 %P 359-375 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320570?dopt=Abstract %R 10.3233/JAD-171183 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Characterizing Aging, Mild Cognitive Impairment, and Dementia with Blood-Based Biomarkers and Neuropsychology. %A Kleinschmidt, Martin %A Schoenfeld, Robby %A Göttlich, Claudia %A Bittner, Daniel %A Metzner, Jürgen Erich %A Leplow, Bernd %A Demuth, Hans-Ulrich %K Activities of Daily Living %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Aging %K Amyloid beta-Peptides %K Analysis of Variance %K Apolipoproteins E %K Biomarkers %K Case-Control Studies %K Cognitive Dysfunction %K Cross-Sectional Studies %K Cytokines %K Dementia %K Female %K Humans %K Male %K Memory Disorders %K Middle Aged %K Neuropsychological Tests %K Young Adult %X

BACKGROUND: Current treatment in Alzheimer's disease (AD) is initiated at a stage where the brain already has irreversible structural deteriorations. Therefore, the concept of treatment prior to obvious cognitive deficits has become widely accepted, and simple biochemical tests to discriminate normal aging from prodromal or demented stages are now common practice.

OBJECTIVE: The objective of the study was the differentiation of controls, mild cognitive impairment (MCI) and AD patients by novel blood-based assays in combination with neuropsychological tests.

METHODS: In a cross-sectional study, 143 subjects aged 18 to 85 years were recruited. All participants were classified by a comprehensive neuropsychological assessment. Blood samples were analyzed for several amyloid-β (Aβ) species, pro-inflammatory markers, anti-Aβ autoantibodies, and ApoE allele status, respectively.

RESULTS: Plasma Aβ1-42 was significantly decreased in MCI and AD compared to age-matched controls, whereas Aβ1-40 did not differ, but increases with age in healthy controls. The Aβ1-42 to Aβ1-40 ratio was stepwise decreased from age-matched controls via MCI to AD, and shows a clear correlation with memory scores. Reduced Aβ1-42 and Aβ1-42 to Aβ1-40 ratio have strongly correlated with carrying ApoE ɛ4 allele. Autoantibodies against pyroglutamate-modified Aβ, but only a certain subclass, were significantly decreased in AD compared to MCI and age-matched controls, whereas autoantibodies against the unmodified N-terminus of Aβ did not differ.

CONCLUSION: Comprehensive sample preparation and assay standardization enable reliable usage of plasma Aβ for diagnosis of MCI and AD. Anti-pGlu-Aβ autoantibodies correlate with cognition, but not with ApoE, supporting the associated plasma Aβ analysis with additional and independent information.

%B J Alzheimers Dis %V 50 %P 111-26 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639953?dopt=Abstract %R 10.3233/JAD-143189