Abstract
Aim:
Transgenic mice that overexpress human amyloid precursor protein with Swedish or London (APPswe or APPlon) mutations have been widely used for preclinical Alzheimer's disease (AD) drug development. AD patients, however, rarely possess these mutations or overexpress APP.
Results:
We developed a sensitive ELISA that specifically and accurately measures low levels of endogenous Aβ40 in mouse plasma, brain and CSF. In wild-type mice treated with a bispecific anti-TfR/BACE1 antibody, significant Aβ reductions were observed in the periphery and the brain. APPlon transgenic mice showed a slightly less reduction, whereas APPswe mice did not have any decrease.
Conclusion:
This sensitive and well-characterized mouse Aβ40 assay enables the use of wild-type mice for preclinical PK/PD and efficacy studies of potential AD therapeutics.
Keywords:
Alzheimer's disease; BACE1; ELISA; PD biomarker; mouse abeta; therapeutic antibody; transferrin receptor.
MeSH terms
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Alzheimer Disease / drug therapy*
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Alzheimer Disease / pathology
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Amyloid Precursor Protein Secretases / immunology
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Amyloid beta-Peptides / analysis*
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Amyloid beta-Peptides / antagonists & inhibitors
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Amyloid beta-Peptides / blood
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Amyloid beta-Peptides / cerebrospinal fluid
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Animals
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Antibodies, Bispecific / immunology
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Antibodies, Bispecific / therapeutic use
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Aspartic Acid Endopeptidases / immunology
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Biomarkers / analysis
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Biomarkers / blood
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Biomarkers / cerebrospinal fluid
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Brain / drug effects
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Brain / pathology
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Disease Models, Animal
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Drug Discovery / methods*
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Enzyme-Linked Immunosorbent Assay / methods
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Humans
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Mice
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Mice, Transgenic
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Peptide Fragments / analysis*
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Peptide Fragments / antagonists & inhibitors
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Peptide Fragments / blood
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Peptide Fragments / cerebrospinal fluid
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Receptors, Transferrin / immunology
Substances
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Amyloid beta-Peptides
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Antibodies, Bispecific
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Biomarkers
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Peptide Fragments
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Receptors, Transferrin
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Tfrc protein, mouse
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amyloid beta-protein (1-40)
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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Bace1 protein, mouse