Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer's disease neurons: implications for mitochondrial dysfunction and neuronal damage

• Published in: Human molecular genetics Vol. 21; no. 11; pp. 2538 - 2547
• Main Authors: MANCZAK, Maria, HEMACHANDRA REDDY, P
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-06-2012
• Subjects: Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Animals; Axonal transport; beta -Amyloid; Binding Sites; Biological and medical sciences; Brain; Cognitive ability; Cortex (frontal); Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Fluorescent Antibody Technique; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; GTP Phosphohydrolases - genetics; GTP Phosphohydrolases - metabolism; Guanosinetriphosphatase; Humans; Immunofluorescence; Immunoprecipitation; Medical sciences; Mice; Mice, Transgenic; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Mitochondria; Mitochondria - metabolism; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Molecular and cellular biology; Neurodegeneration; Neurodegenerative diseases; Neurology; Neurons; Neurons - metabolism; Phosphorylation; Presenilin 1; Tau protein; tau Proteins - genetics; tau Proteins - metabolism; Nervous system diseases; Mitochondria; Neuron; Tau protein; Alzheimer disease; Dysfunction; Central nervous system disease; Genetics; Degenerative disease; Lesion; Fission; Cerebral disorder
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/dds072

We recently reported increased mitochondrial fission and decreased fusion, increased amyloid beta (Aβ) interaction with the mitochondrial fission protein Drp1, increased mitochondrial fragmentation, impaired axonal transport of mitochondria and synaptic degeneration in neurons affected by AD. In the present study, we extended our previous investigations to determine whether phosphorylated tau interacts with Drp1 and to elucidate mitochondrial damage in the progression of AD. We also investigated GTPase activity, which is critical for mitochondrial fragmentation, in postmortem brain tissues from patients with AD and brain tissues from APP, APP/PS1 and 3XTg.AD mice. Using co-immunoprecipitation and immunofluorescence analyses, for the first time, we demonstrated the physical interaction between phosphorylated tau and Drp1. Mitochondrial fission-linked GTPase activity was significantly elevated in the postmortem frontal cortex tissues from AD patients and cortical tissues from APP, APP/PS1 and 3XTg.AD mice. On the basis of these findings, we conclude that Drp1 interacts with Aβ and phosphorylated tau, likely leading to excessive mitochondrial fragmentation, and mitochondrial and synaptic deficiencies, ultimately possibly leading to neuronal damage and cognitive decline. Treatment designed to reduce the expression of Drp1, Aβ and/or phosphorylated tau may decrease the interaction between Drp1 and phosphorylated tau and the interaction between Drp1 and Aβ, conferring protection to neurons from toxic insults of excessive Drp1, Aβ and/or phosphorylated tau.