Characterization of a sensitive mouse Aβ40 PD biomarker assay for Alzheimer's disease drug development in wild-type mice.
OBJECTIVE
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.


CONCLUSIONS
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.
Departments of Biochemical & Cellular Pharmacology & Neuroscience, Genentech, Inc., South San Francisco, CA, USA.
Yanmei
Y
Lu
Departments of Biochemical & Cellular Pharmacology & Neuroscience, Genentech, Inc., South San Francisco, CA, USA.
Kwame
K
Hoyte
Departments of Biochemical & Cellular Pharmacology & Neuroscience, Genentech, Inc., South San Francisco, CA, USA.
William H
WH
Montgomery
Departments of Biochemical & Cellular Pharmacology & Neuroscience, Genentech, Inc., South San Francisco, CA, USA.
Wilman
W
Luk
Departments of Biochemical & Cellular Pharmacology & Neuroscience, Genentech, Inc., South San Francisco, CA, USA.
Dongping
D
He
Departments of Neuroscience, Genentech, Inc., South San Francisco, CA, USA.
William J
WJ
Meilandt
Departments of Neuroscience, Genentech, Inc., South San Francisco, CA, USA.
Y Joy Yu
YJ
Zuchero
Departments of Neuroscience, Genentech, Inc., South San Francisco, CA, USA.
Jasvinder K
JK
Atwal
Departments of Neuroscience, Genentech, Inc., South San Francisco, CA, USA.
Kimberly
K
Scearce-Levie
Departments of Neuroscience, Genentech, Inc., South San Francisco, CA, USA.
Ryan J
RJ
Watts
Departments of Biochemical & Cellular Pharmacology & Neuroscience, Genentech, Inc., South San Francisco, CA, USA.
Laura E
LE
DeForge
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000276:immunology; D016229:Amyloid beta-Peptides / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000097:blood / Q000134:cerebrospinal fluid; D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000627:therapeutic use; D016282:Aspartic Acid Endopeptidases / Q000276:immunology; D015415:Biomarkers / Q000032:analysis / Q000097:blood / Q000134:cerebrospinal fluid; D001921:Brain / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D055808:Drug Discovery / Q000379:methods*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000097:blood / Q000134:cerebrospinal fluid; D011990:Receptors, Transferrin / Q000276:immunology
D016229:Amyloid beta-Peptides; D018033:Antibodies, Bispecific; D015415:Biomarkers; D010446:Peptide Fragments; D011990:Receptors, Transferrin; C480029:Tfrc protein, mouse; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
Alzheimer's disease; BACE1; ELISA; PD biomarker; mouse abeta; therapeutic antibody; transferrin receptor