Beta-amyloid1-42 gene transfer model exhibits intraneuronal amyloid, gliosis, tau phosphorylation, and neuronal loss.
Alzheimer disease is characterized by extracellular beta-amyloid (Abeta) plaques and intracellular inclusions containing neurofibrillary tangles of phospho-Tau and intraneuronal Abeta associated with neuronal cell death. We generated a novel gene transfer animal model using lentiviral Abeta(1-42) that resulted in intracellular but not extracellular Abeta accumulations in the targeted rat primary motor cortex. Expression of intracellular Abeta(1-42) led to pathological changes seen in human Alzheimer disease brains, including cell death, inflammatory signs, activation of two Tau kinases, and Tau hyperphosphorylation. Promoting clearance of lentiviral Abeta(1-42) reversed these effects, demonstrating that intraneuronal Abeta(1-42) is a toxic peptide that lies upstream of Tau modification. These studies reveal the role of intracellular Abeta(1-42) in a novel gene transfer animal model, which is a useful tool to study intraneuronal Abeta(1-42)-induced pathology in the absence of extracellular plaques. Targeted delivery of Abeta will allow speedy delineation of pathological mechanisms associated with specific neurodegenerative lesions.
Rebeck
G William
GW
Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20007, USA.
Hoe
Hyang-Sook
HS
Moussa
Charbel E-H
CE
D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016923:Cell Death / Q000502:physiology*; D002470:Cell Survival; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D051360:Cyclin-Dependent Kinase 5; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3