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P4‐474: CHARACTERIZATION OF A NOVEL HUMANIZED WILD‐TYPE TAU EXPRESSING MOUSE MODEL IN HIGH‐AMYLOID BACKGROUND OF 5XFAD MICE
Author(s) -
Cynis Holger,
Barendrecht Susan,
Geissler Stefanie,
Demuth Hans-Ulrich,
Schilling Stephan,
Schreurs An,
Balschun Detlef
Publication year - 2019
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2019.08.020
Subject(s) - morris water navigation task , neuropathology , western blot , wild type , neuroprotection , genetically modified mouse , amyloid (mycology) , elevated plus maze , pathology , medicine , neuroscience , biology , endocrinology , transgene , hippocampus , disease , anxiety , mutant , gene , biochemistry , psychiatry
important with more detailed understanding of the amylogenic pathway and the role of different Ab peptide species. For that purpose, we developed and validated a novel mass spectrometric method to quantify six endogenous Ab species of different lengths, namely Ab1-34, Ab1-37, Ab1-38, Ab1-39, Ab1-40 and Ab1-42. The aim of the study was to investigate if absolute concentrations and/or ratios of these Ab peptides are different in CSF from clinically diagnosed AD patients compared with control subjects. Methods: Absolute quantification of the above-mentioned six Ab peptides was performed using parallel reaction monitoring on a hybrid quadrupole-orbitrap mass spectrometer. In this first study, 97 CSF samples were analyzed, of which 47 samples were from clinically diagnosed AD patients and 50 samples were from cognitively normal control subjects. Group analyses were performed using unpaired t-test, as well as ROC and correlation analyses. Results: There was a significant decrease in the CSF concentration of Ab1-42, as well as in all ratios involving this peptide divided by the concentration of any of the C-terminally truncated Ab forms (Ab1-42/Ab1-40, Ab1-42/Ab1-39, Ab1-42/Ab1-38,Ab1-42/Ab1-37 and Ab1-42/Ab1-34), in AD patients compared with controls (P <0.0001 for all comparisons). CSF concentrations of the C-terminally truncated Ab forms were similar in the two groups and highly correlated. The best-performing biomarker combination for distinguishing AD patients from controls was Ab1-42/Ab1-40 with an area under the curve of 0.9632 (P <0.0001). Conclusions: These results show that, in contrast to Ab1-42, the Ab1-34, Ab1-37, Ab1-38, Ab1-39 and Ab1-40 peptide concentrations in CSF are unaffected by cerebral Ab pathology in patients with the sporadic form of AD. Instead, assessment of these peptides may be useful in studies on familial AD (FAD), to further understand the effects of different mutations, and in pharmacodynamic studies to assess biochemical effects of AD therapies targeting amyloid precursor protein-processing in clinical trials.