Tau Mislocalization to Dendritic Spines Mediates Synaptic Dysfunction Independently of Neurodegeneration

Brian R. Hoover, Miranda N. Reed, Jianjun Su, Rachel D. Penrod, Linda A. Kotilinek, Marianne K. Grant, Rose Pitstick, George A. Carlson, Lorene M Lanier, Li Lian Yuan, Karen H Ashe, Dezhi Liao

Research output: Contribution to journalArticle

400 Citations (Scopus)

Abstract

The microtubule-associated protein tau accumulates in Alzheimer's and other fatal dementias, which manifest when forebrain neurons die. Recent advances in understanding these disorders indicate that brain dysfunction precedes neurodegeneration, but the role of tau is unclear. Here, we show that early tau-related deficits develop not from the loss of synapses or neurons, but rather as a result of synaptic abnormalities caused by the accumulation of hyperphosphorylated tau within intact dendritic spines, where it disrupts synaptic function by impairing glutamate receptor trafficking or synaptic anchoring. Mutagenesis of 14 disease-associated serine and threonine amino acid residues to create pseudohyperphosphorylated tau caused tau mislocalization while creation of phosphorylation-deficient tau blocked the mistargeting of tau to dendritic spines. Thus, tau phosphorylation plays a critical role in mediating tau mislocalization and subsequent synaptic impairment. These data establish that the locus of early synaptic malfunction caused by tau resides in dendritic spines.

Original languageEnglish (US)
Pages (from-to)1067-1081
Number of pages15
JournalNeuron
Volume68
Issue number6
DOIs
StatePublished - Dec 22 2010

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Dendritic Spines
Phosphorylation
Neurons
Microtubule-Associated Proteins
Glutamate Receptors
Brain Diseases
Threonine
Prosencephalon
Mutagenesis
Synapses
Serine
Dementia
Amino Acids

Cite this

Hoover, B. R., Reed, M. N., Su, J., Penrod, R. D., Kotilinek, L. A., Grant, M. K., ... Liao, D. (2010). Tau Mislocalization to Dendritic Spines Mediates Synaptic Dysfunction Independently of Neurodegeneration. Neuron, 68(6), 1067-1081. https://doi.org/10.1016/j.neuron.2010.11.030

Tau Mislocalization to Dendritic Spines Mediates Synaptic Dysfunction Independently of Neurodegeneration. / Hoover, Brian R.; Reed, Miranda N.; Su, Jianjun; Penrod, Rachel D.; Kotilinek, Linda A.; Grant, Marianne K.; Pitstick, Rose; Carlson, George A.; Lanier, Lorene M; Yuan, Li Lian; Ashe, Karen H; Liao, Dezhi.

In: Neuron, Vol. 68, No. 6, 22.12.2010, p. 1067-1081.

Research output: Contribution to journalArticle

Hoover, BR, Reed, MN, Su, J, Penrod, RD, Kotilinek, LA, Grant, MK, Pitstick, R, Carlson, GA, Lanier, LM, Yuan, LL, Ashe, KH & Liao, D 2010, 'Tau Mislocalization to Dendritic Spines Mediates Synaptic Dysfunction Independently of Neurodegeneration', Neuron, vol. 68, no. 6, pp. 1067-1081. https://doi.org/10.1016/j.neuron.2010.11.030
Hoover, Brian R. ; Reed, Miranda N. ; Su, Jianjun ; Penrod, Rachel D. ; Kotilinek, Linda A. ; Grant, Marianne K. ; Pitstick, Rose ; Carlson, George A. ; Lanier, Lorene M ; Yuan, Li Lian ; Ashe, Karen H ; Liao, Dezhi. / Tau Mislocalization to Dendritic Spines Mediates Synaptic Dysfunction Independently of Neurodegeneration. In: Neuron. 2010 ; Vol. 68, No. 6. pp. 1067-1081.
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