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Author Notes:

Correspondence: Sam Gandy, M.D., Ph.D., Departments of Neurology and Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1137, New York, NY 10029 USA. Email: samuel.gandy@mssm.edu

Authors' Contributions: AJS, JWS, and ALL contributed equally

S.G., J.W.S., and A.L. prepared the manuscript.

J.W.S., W.B., A.L.L. and J.S. performed statistical analysis of all data.

See publication for full list of Author Contributions.

Acknowledgments: The authors would like to thank Tabansi Kawafumu and Emily Sluzas for technical assistance on the project.

Disclosures: MEE: Grantee for study of latrepirdine mechanisms of action in Huntington’s Disease at Medivation.

SG: Safety Monitoring Committee at J&J/Elan; Consultant and grantee at Diagenic, Amicus

A.S. is founder of Neuronostics.

G.K. is the founder of Acumen Pharmaceuticals.


Research Funding:

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.

T.A. was supported by National Institute on Aging grant P50AG017623 (A.I. Pack, PI).

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.

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.


  • (1) Amyloid
  • (2) Alzheimer’s Disease
  • (3) Spatial Recognition
  • (4) Days-to-Criterion
  • (5) Amyloid Precursor Protein

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

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Journal Title:

Annals of Neurology


Volume 68, Number 2


, Pages 220-230

Type of Work:

Article | Post-print: After Peer Review


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.

Copyright information:

© 2010 American Neurological Association

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