Early-onset Amyloid Deposition and Cognitive Deficits in Transgenic Mice Expressing a Double Mutant Form of Amyloid Precursor Protein 695

M Azhar Chishti ,Céline Morissette,Catherine Bergeron,Julie Paquette,Patrick Horne,Paul E Fraser,Francine Gervais,Dun-Shen Yang,James Loukides,Sherry Turner,Christopher Janus,Jacqueline Pearson,Mariagrazia Grilli,George A Carlson,Gianluca Lozza,David Westaway,Suzanne Kunicki,Amie L Phinney,Robert Strome,Peter St George-Hyslop ,Noah B Zuker ,Jacqueline A French

doi:10.1074/jbc.m100710200

Abstract

We have created early-onset transgenic (Tg) models by exploiting the synergistic effects of familial Alzheimer's disease mutations on amyloid beta-peptide (Abeta) biogenesis. TgCRND8 mice encode a double mutant form of amyloid precursor protein 695 (KM670/671NL+V717F) under the control of the PrP gene promoter. Thioflavine S-positive Abeta amyloid deposits are present at 3 months, with dense-cored plaques and neuritic pathology evident from 5 months of age. TgCRND8 mice exhibit 3,200-4,600 pmol of Abeta42 per g brain at age 6 months, with an excess of Abeta42 over Abeta40. High level production of the pathogenic Abeta42 form of Abeta peptide was associated with an early impairment in TgCRND8 mice in acquisition and learning reversal in the reference memory version of the Morris water maze, present by 3 months of age. Notably, learning impairment in young mice was offset by immunization against Abeta42 (Janus, C., Pearson, J., McLaurin, J., Mathews, P. M., Jiang, Y., Schmidt, S. D., Chishti, M. A., Horne, P., Heslin, D., French, J., Mount, H. T. J., Nixon, R. A., Mercken, M., Bergeron, C., Fraser, P. E., St. George-Hyslop, P., and Westaway, D. (2000) Nature 408, 979-982). Amyloid deposition in TgCRND8 mice was enhanced by the expression of presenilin 1 transgenes including familial Alzheimer's disease mutations; for mice also expressing a M146L+L286V presenilin 1 transgene, amyloid deposits were apparent by 1 month of age. The Tg mice described here suggest a potential to investigate aspects of Alzheimer's disease pathogenesis, prophylaxis, and therapy within short time frames.

Highlights

Alzheimer’s disease, the most common cause of dementia, has a complex etiology involving both genetic and environmental determinants
Factors Affecting amyloid precursor protein (APP) Transgenesis— transgenesis is generally regarded as a routine technique, the APP gene, first cloned over a decade ago, can be seen to present particular challenges
We modified a number of parameters in our experimental design in an effort to reduce the “noise” from these confounding effects and thereby facilitate study of the pathogenic attributes of the A␤ peptide; such pathogenic attributes are clearly suggested by genetic, neuropathological, and toxicological studies [12,13,14, 48]

Summary

Introduction

Alzheimer’s disease, the most common cause of dementia, has a complex etiology involving both genetic and environmental determinants. The ⑀4 allele of the ApoE gene, which is correlated with increased susceptibility to late-onset AD [10], is found to enhance the formation of mature plaques in certain APP transgenic mice [11] These genetic data indicate elevated A␤ biogenesis or accumulation is likely a crucial pathogenic event in all forms of AD (i.e. both familial and sporadic AD). We describe a new line of transgenic mice that exhibits deposition of A␤-amyloid and robust cognitive deficits by the age of 3 months These mice have a demonstrated utility for assessing procedures that interfere with amyloidogenesis [1] and may serve as a platform to create more sophisticated models of AD

Methods

Results

Conclusion