Journal article
Days-to-criterion as an indicator of toxicity associated with human Alzheimer amyloid-β oligomers
Annals of neurology, Vol.68(2), pp.220-230
08/2010
DOI: 10.1002/ana.22052
PMCID: PMC3094694
PMID: 20641005
Abstract
Objective
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 Alzheimer disease (AD). To date, most in vivo studies of oAβ/ADDLs have involved injection of assemblies purified from the cerebrospinal fluid of human subjects with AD 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 amyloid precursor protein (APP) and presenitin1 (PS1) 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/ADDLs by enzyme-linked immunosorbent assay (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, although only 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 nontransgenic 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.
Details
- Title: Subtitle
- Days-to-criterion as an indicator of toxicity associated with human Alzheimer amyloid-β oligomers
- Creators
- Sam Gandy - Departments of Neurology and Psychiatry and Alzheimer’s Disease Research Center, Mount Sinai School of Medicine, New York, NY 10029Adam J Simon - Neuronostics, Yardley, PA, 19067John W Steele - Departments of Neurology and Psychiatry and Alzheimer’s Disease Research Center, Mount Sinai School of Medicine, New York, NY 10029Alex L Lublin - Departments of Neurology and Psychiatry and Alzheimer’s Disease Research Center, Mount Sinai School of Medicine, New York, NY 10029James J Lah - Department of Neurology, Center for Neurodegenerative Disease, Emory University, Atlanta, GA 30322Lary C Walker - Department of Neurology, Center for Neurodegenerative Disease, Emory University, Atlanta, GA 30322Allan I Levey - Department of Neurology, Center for Neurodegenerative Disease, Emory University, Atlanta, GA 30322Grant A Krafft - Acumen Pharmaceuticals, Inc., Livermore, CA 94551Efrat Levy - Center for Dementia Research, New York University and the Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962Frédéric Checler - Institute de Pharmacologie Moleculaire et Cellulaire, Valbonne, France 06560Charles Glabe - Department of Neurology, University of California Irvine School of Medicine, CA 92697Warren Bilker - Department of Psychiatry, University of Pennsylvania, Philadelphia PA 19104Ted Abel - Department of Biology, University of Pennsylvania, Philadelphia PA 19104James Schmeidler - Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029Michelle E Ehrlich - Departments of Neurology and Pediatrics and Alzheimer’s Disease Research Center, Mount Sinai School of Medicine, New York, NY 10029
- Resource Type
- Journal article
- Publication Details
- Annals of neurology, Vol.68(2), pp.220-230
- DOI
- 10.1002/ana.22052
- PMID
- 20641005
- PMCID
- PMC3094694
- NLM abbreviation
- Ann Neurol
- ISSN
- 0364-5134
- eISSN
- 1531-8249
- Grant note
- T32 GM062754-11 || GM / National Institute of General Medical Sciences : NIGMS P50 AG025688-07 || AG / National Institute on Aging : NIA P50 AG005138-21A1 || AG / National Institute on Aging : NIA P01 AG010491-14 || AG / National Institute on Aging : NIA
- Language
- English
- Date published
- 08/2010
- Academic Unit
- Molecular Physiology and Biophysics; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
- Record Identifier
- 9984065826602771
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