β-Amyloid1-42 gene transfer model exhibits intraneuronal amyloid, gliosis, tau phosphorylation, and neuronal loss

Abstract

Alzheimer disease is characterized by extracellular β-amyloid (Aβ) plaques and intracellular inclusions containing neurofibrillary tangles of phospho-Tau and intraneuronal Aβ associated with neuronal cell death. We generated a novel gene transfer animal model using lentiviral Aβ1-42 that resulted in intracellular but not extracellular Aβ accumulations in the targeted rat primary motor cortex. Expression of intracellular Aβ1-42 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 Aβ1-42 reversed these effects, demonstrating that intraneuronal Aβ1-42 is a toxic peptide that lies upstream of Tau modification. These studies reveal the role of intracellular Aβ1-42 in a novel gene transfer animal model, which is a useful tool to study intraneuronal Aβ1-42-induced pathology in the absence of extracellular plaques. Targeted delivery of Aβ will allow speedy delineation of pathological mechanisms associated with specific neurodegenerative lesions. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.