Hyperphosphorylated Tau and Neurofilament and Cytoskeletal Disruptions in Mice Overexpressing Human p25, an Activator of cdk5

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 97; no. 6; pp. 2910 - 2915
• Main Authors: Ahlijanian, M K, Barrezueta, N X, Williams, R D, Jakowski, A, Kowsz, K P, McCarthy, S, Coskran, T, Carlo, A, Seymour, P A, Burkhardt, J E, Nelson, R B, McNeish, J D
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 14.03.2000; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Age Factors; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amygdala; Animals; Antibodies; Axons; Biological Sciences; Brain; Brain - pathology; Brain - ultrastructure; cdk5 kinase; cdk5 protein; Cerebellum; Cyclin-Dependent Kinase 5; Cyclin-Dependent Kinases - physiology; Cytoskeleton - metabolism; Epitopes; Female; Humans; Immunohistochemistry; Male; Mazes; Medical disorders; Mice; Mice, Transgenic; Microscopy, Electron; Nerve Tissue Proteins - metabolism; Neurodegenerative diseases; Neurofilament Proteins - metabolism; Neurons; Pharmacology; Phosphorylation; Proteins; Rodents; Sex Factors; Silver Staining; tau Proteins - metabolism; Transgenic animals
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.040577797

Hyperphosphorylation of microtubule-associated proteins such as tau and neurofilament may underlie the cytoskeletal abnormalities and neuronal death seen in several neurodegenerative diseases including Alzheimer's disease. One potential mechanism of microtubule-associated protein hyperphosphorylation is augmented activity of protein kinases known to associate with microtubules, such as cdk5 or GSK3β . Here we show that tau and neurofilament are hyperphosphorylated in transgenic mice that overexpress human p25, an activator of cdk5. The p25 transgenic mice display silver-positive neurons using the Bielschowsky stain. Disturbances in neuronal cytoskeletal organization are apparent at the ultrastructural level. These changes are localized predominantly to the amygdala, thalamus/hypothalamus, and cortex. The p25 transgenic mice display increased spontaneous locomotor activity and differences from control in the elevated plus-maze test. The overexpression of an activator of cdk5 in transgenic mice results in increased cdk5 activity that is sufficient to produce hyperphosphorylation of tau and neurofilament as well as cytoskeletal disruptions reminiscent of Alzheimer's disease and other neurodegenerative diseases.