Memory-related deficits following selective hippocampal expression of Swedish mutation amyloid precursor protein in the rat

• Published in: Experimental neurology Vol. 200; no. 2; pp. 371 - 377
• Main Authors: Gong, Yan, Meyer, Edwin M., Meyers, Craig A., Klein, Ronald L., King, Michael A., Hughes, Jeffrey A.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01-08-2006; Elsevier
• Subjects: Adeno-associated virus; Alzheimer Disease - complications; Alzheimer Disease - etiology; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer’s disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Animals; Behavior, Animal; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Fluoresceins; Gene Expression - physiology; Genetic Vectors - physiology; Hippocampus - metabolism; Hippocampus - physiopathology; Hippocampus - virology; Humans; Immunohistochemistry - methods; Inflammation; Injuries of the nervous system and the skull. Diseases due to physical agents; Male; Maze Learning - physiology; Medical sciences; Memory Disorders - etiology; Memory Disorders - pathology; Memory Disorders - physiopathology; Memory-related behavior; Mutation; Neurology; Organic Chemicals; Peptide Fragments - metabolism; Rats; Rats, Sprague-Dawley; Thiazoles; Traumas. Diseases due to physical agents; Adeno-associated virus; Inflammation; Alzheimer’s disease; Amyloid precursor protein; Memory-related behavior; Memory disorder; Cognitive disorder; Rat; Alzheimer disease; Spine; Central nervous system; Injection site; Betaherpesvirinae; Swedish; Osteoarticular system; Degenerative disease; Amyloid; Behavior; Serotype; Aves; Vector; Alzheimer's disease; Human; Cytomegalovirus; Nervous system diseases; Senile plate; Herpesviridae; Rodentia; Long term; Cerebral disorder; Infection; Virus; Vertebrata; Dentate gyrus; Mammalia; Gliosis; Neuron; Complementary DNA; Animal; Viral disease; Central nervous system disease; Chicken; Transduction; Mutation; Hippocampus; Spatial memory
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2006.02.136

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. Aβ1–42 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.