Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo.
Hyperphosphorylated forms of the microtubule-associated protein (MAP) tau accumulate in Alzheimer's disease and related tauopathies and are thought to have an important role in neurodegeneration. However, the mechanisms through which phosphorylated tau induces neurodegeneration have remained elusive. Here, we show that tau-induced neurodegeneration is associated with accumulation of filamentous actin (F-actin) and the formation of actin-rich rods in Drosophila and mouse models of tauopathy. Importantly, modulating F-actin levels genetically leads to dramatic modification of tau-induced neurodegeneration. The ability of tau to interact with F-actin in vivo and in vitro provides a molecular mechanism for the observed phenotypes. Finally, we show that the Alzheimer's disease-linked human beta-amyloid protein (Abeta) synergistically enhances the ability of wild-type tau to promote alterations in the actin cytoskeleton and neurodegeneration. These findings raise the possibility that a direct interaction between tau and actin may be a critical mediator of tau-induced neurotoxicity in Alzheimer's disease and related disorders.
Fulga
Tudor A
TA
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Harvard New Research Building Room 652, 77 Louis Pasteur Avenue, Boston, MA 02115, USA. Tudor_Fulga@hms.harvard.edu
Elson-Schwab
Ilan
I
Khurana
Vikram
V
Steinhilb
Michelle L
ML
Spires
Tara L
TL
Hyman
Bradley T
BT
Feany
Mel B
MB
D000199:Actins / Q000187:drug effects / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004330:Drosophila; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D016875:tau Proteins / Q000378:metabolism* / Q000494:pharmacology
D000199:Actins; D016229:Amyloid beta-Peptides; C054369:MAPT protein, human; D016875:tau Proteins