Memory-related deficits following selective hippocampal expression of Swedish mutation amyloid precursor protein in the rat.
The gene encoding for the Swedish double mutation (K595N/M596L) of amyloid precursor protein (APP695Swe) was expressed bilaterally in adult rat hippocampus to determine its long-term effects on memory-related behavior as well as amyloid deposition. Recombinant adeno-associated viral serotype 2 (rAAV2) vectors were injected that contained either non-expressing DNA or cDNA encoding for APP695Swe under control of a chicken beta actin/cytomegalovirus promoter/enhancer. Immunolabeling human APP with the antibody 6E10 was observed throughout the cytoplasm of aspiny and, to a lesser extent, spine-bearing hippocampal neurons 6 and 12 months post-injection of the APP695Swe but not control vector. Abeta1-42 immunolabeling was identified in unusual immunoreactive objects within the hilus of the dentate gyrus and in the granule cell layer, proximal to the injection site. At 12 months post-transduction, rats that received the APP695Swe gene also demonstrated significant deficits in the acquisition and probe components of the spatial-memory-related Morris water task compared to control animals. These behavioral deficits occurred in the absence of any amyloid plaques, gliosis, or FluoroJade labeling of dying neurons. In conclusion, prolonged and localized APP695Swe expression in hippocampal neurons is sufficient to produce memory deficits without plaque formation or neuronal loss.
Gong
Yan
Y
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, 32610, USA.
Meyer
Edwin M
EM
Meyers
Craig A
CA
Klein
Ronald L
RL
King
Michael A
MA
Hughes
Jeffrey A
JA
D000544:Alzheimer Disease / Q000150:complications / Q000209:etiology / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal; D052160:Benzothiazoles; D004195:Disease Models, Animal; D005452:Fluoresceins; D015870:Gene Expression / Q000502:physiology; D005822:Genetic Vectors / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology* / Q000821:virology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D009930:Organic Chemicals; D010446:Peptide Fragments / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D052160:Benzothiazoles; D005452:Fluoresceins; D009930:Organic Chemicals; D010446:Peptide Fragments; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); C435731:fluoro jade; C009462:thioflavin T