Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 285, Issue 10, Pages 7440-7446Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.083915
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- NIA NIH HHS [P01 AG030128] Funding Source: Medline
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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.
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