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.