Days-to-criterion as an indicator of toxicity associated with human Alzheimer amyloid-β oligomers

• Type of Material: Article
• Authors: Sam Gandy, Mount Sinai School of Medicine; Adam J. Simon, Neuronostics; John W. Steele, Mount Sinai School of Medicine; Alex L. Lublin, Mount Sinai School of Medicine; James J Lah, Emory University; Lary C Walker, Emory University; Allan I Levey, Emory University; Grant A. Krafft, Acumen Pharmaceuticals, Inc.; Efrat Levy, New York University; Frederic Checler, Institute de Pharmacologie Moleculaire et Cellulaire; Charles Glabe, University of California; Warren Bilker, University of Pennsylvania; Ted Abel, University of Pennsylvania; James Schmeidler, Mount Sinai School of Medicine; Michelle E. Ehrlich, Mount Sinai School of Medicine
• Language: English
• Date: 2010-08
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2010 American Neurological Association
• Final Published Version (URL): http://onlinelibrary.wiley.com/doi/10.1002/ana.22052/abstract
• Title of Journal or Parent Work: Annals of Neurology
• ISSN: 0364-5134
• Volume: 68
• Issue: 2
• Start Page: 220
• End Page: 230
• Grant/Funding Information: J.W.S. is a trainee in the Integrated Pharmacological Sciences Training Program supported by grant T32GM062754 from the National Institute of General Medical Sciences.; T.A. was supported by National Institute on Aging grant P50AG017623 (A.I. Pack, PI).; S.G., A.L.L., J.W.S. and M.E.E. were supported by the Cure Alzheimer’s Fund, VA MERIT review grant 1I01BX000348-01, and National Institute on Aging grant P01AG10491.; J.J.L. and A.I.L. were supported by National Institute on Aging grant P50AG025688 and L.C.W. was supported by National Center for Research Resources grant RR-00165.; J.S. was supported by National Institute on Aging grants P50AG05138 and P01AG02219.
• Keywords: (3) Spatial Recognition; (1) Amyloid; (2) Alzheimer’s Disease; (4) Days-to-Criterion; (5) Amyloid Precursor Protein
• Research Categories: Biology, Neuroscience

Abstract

Objectives Recent evidence suggests that high molecular weight soluble oligomeric Aβ (oAβ) assemblies (also known as Aβ-derived diffusible ligands, or ADDLs) may represent a primary neurotoxic basis for cognitive failure in AD. To date, in vivo studies of oAβ/ADDLs have involved injection of assemblies purified from the cerebrospinal fluid (CSF) of human subjects with Alzheimer’s disease or from the conditioned media of Aβ-secreting cells into experimental animals. We sought to study the bioactivities of endogenously formed oAβ/ADDLs generated in situ from the physiological processing of human APP transgenes. Methods We produced and histologically characterized single transgenic mice overexpressing APPE693Q or APPE693Q X PS1ΔE9 bigenic mice. APPE693Q mice were studied in the Morris water maze (MWM) task at 6 and 12 months of age. Following the second MWM evaluation, mice were sacrificed, and brains were assayed for Aβtotal, Aβ40, Aβ42, and oAβ/ADDL by ELISA and were also histologically examined. Based on results from the oAβ/ADDL ELISA, we assigned individual APPE693Q mice to either an “undetectable oAβ/ADDLs group” or a “readily detectable oAβ/ADDLs group”. A days-to-criterion (DTC) analysis was used to determine delays in acquisition of the MWM task. Results Both single transgenic and bigenic mice developed intraneuronal accumulation of APP/Aβ, though only Dutch APPE693Q X PS1Δ9 bigenic mice developed amyloid plaques. The APPE693Q mice did not develop amyloid plaques at any age studied, up to 30 months. APPE693Q mice were tested for spatial learning and memory, and only 12-month old APPE693Q mice with readily detectable oAβ/ADDLs displayed a significant delay in acquisition of the MWM task when compared to NTg littermates. Interpretation These data suggest that cerebral oAβ/ADDL assemblies generated in brain in situ from human APP transgenes may be associated with cognitive impairment. We propose that a DTC analysis may be a sensitive method for assessing the cognitive impact in mice of endogenously generated oligomeric human Aβ assemblies.