A transgenic rat model of Alzheimer's disease with extracellular Abeta deposition.
Many transgenic mouse models of Alzheimer's disease (AD) that deposit amyloid (Abeta) have been produced, but development of an Abeta-depositing rat model has not been successful. Here, we describe a rat model with extracellular fibrillar Abeta deposition. Two lines of Sprague Dawley rats with transgenes expressing human amyloid precursor protein (APP) with the familial AD (FAD) mutations K670N/M671L and K670N/M671L/V717I were crossed. Abeta production in the double homozygous rats was sufficient for deposition by 17-18 months of age. The age of onset of Abeta deposition was reduced by crossing in a third rat line carrying a human presenilin-1 (PS-1) transgene with the FAD M146V mutation. The triple homozygous line had an onset of Abeta deposition by 7 months of age. Deposits appeared similar to those observed in the mouse models and displayed surrounding glial and phosphorylated tau reactivity. Abeta levels measured by ELISA were comparable to those reported in mouse models, suggesting that substantially greater amounts of soluble Abeta are not required in the rat to generate Abeta deposition.
Flood
Dorothy G
DG
Department of CNS Biology, Discovery Research, Cephalon, Inc., West Chester, PA 19380, USA. dflood@cephalon.com
Lin
Yin-Guo
YG
Lang
Diane M
DM
Trusko
Stephen P
SP
Hirsch
James D
JD
Savage
Mary J
MJ
Scott
Richard W
RW
Howland
David S
DS
D017668:Age of Onset; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D045604:Extracellular Fluid / Q000378:metabolism*; D005911:Gliosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D019076:Transgenes / Q000235:genetics; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016875:tau Proteins