Evaluation of the performance of novel Aβ isoforms as theragnostic markers in Alzheimer's disease: from the cell to the patient.
BACKGROUND
Alzheimer's disease (AD) is the most common neurodegenerative disorder in the aging population and is characterized by extracellular plaques in the brain. The last decades have witnessed an explosion in studies of the role of amyloid-β (Aβ) metabolism and aggregation in the pathogenesis of AD which has been translated into novel promising therapies with putative disease-modifying effects.


OBJECTIVE
The aim is to investigate the performance of truncated Aβ isoforms as theragnostic markers in clinical trials.


METHODS
Aβ isoforms were immunoprecipitated from human, mouse and dog cerebrospinal fluid (CSF) or cell media and analyzed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.


RESULTS
Aβ1-14, Aβ1-15, and Aβ1-16 are elevated in cell media and in CSF in response to γ-secretase inhibitor treatment. In a clinical trial including AD patients, Aβ1-14, Aβ1-15, and Aβ1-16 increased dose-dependently in response to treatment with the γ-secretase inhibitor LY450139. In dogs, Aβ1-37 was significantly increased in response to treatment with the γ-secretase modulator E2012.


CONCLUSIONS
The results presented add to the current knowledge on APP processing and that Aβ isoforms can be used as novel biomarkers to monitor anti-Aβ treatments in clinical trials and may be valuable for making a go/no go decision for large and expensive phase 2 or 3 clinical trials.
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden. erik.portelius@neuro.gu.se
Erik
E
Portelius
Mikael K
MK
Gustavsson
Henrik
H
Zetterberg
Ulf
U
Andreasson
Kaj
K
Blennow
D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid*; D053829:Amyloid Precursor Protein Secretases / Q000187:drug effects; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid* / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D020033:Protein Isoforms / Q000134:cerebrospinal fluid*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D001381:Azepines; D004791:Enzyme Inhibitors; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D020033:Protein Isoforms; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine