β-Amyloid1-42 Gene Transfer Model Exhibits Intraneuronal Amyloid, Gliosis, Tau Phosphorylation, and Neuronal Loss

Alzheimer disease is characterized by extracellular beta-amyloid (A beta) plaques and intracellular inclusions containing neurofibrillary tangles of phospho-Tau and intraneuronal A beta associated with neuronal cell death. We generated a novel gene transfer animal model using lentiviral A beta(1-42) that resulted in intracellular but not extracellular A beta accumulations in the targeted rat primary motor cortex. Expression of intracellular A beta(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 A beta(1-42) reversed these effects, demonstrating that intraneuronal A beta(1-42) is a toxic peptide that lies upstream of Tau modification. These studies reveal the role of intracellular A beta(1-42) in a novel gene transfer animal model, which is a useful tool to study intraneuronal A beta(1-42)-induced pathology in the absence of extracellular plaques. Targeted delivery of A beta will allow speedy delineation of pathological mechanisms associated with specific neurodegenerative lesions.