Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration
By B. R. Hoover, M. Reed, Jianjun Su, Rachel D. Penrod, L. Kotilinek, M. Grant, Rose Pitstick, G. Carlson, L. Lanier, L. Yuan and 2 more. Neuron, 2010
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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 mis-targeting 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.
Subfields: Cellular and Molecular Neuroscience, Physiology, Radiology, Nuclear Medicine and Imaging
View Paper: https://www.semanticscholar.org/paper/e20a98eca758004e2c82b3b274f26c2be120a9dd
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Citations in the corpus
- Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020, background): “While phosphorylation at S396 plays a key role in the induction and maintenance of hippocampal LTD [142], mutant tau hyperphosphomimetic Ser/Thr isoforms promotes tau distribution to dendritic spines and impairs synaptic function [143].”
- PET Imaging of Tau Deposition in the Aging Human Brain (2016, neutral): “A potential caveat is that cognitive decline can be observed at a stagewhere only a small number of MTL neurons are affected by tau pathology (Hoover et al., 2010), and soluble and pre-NFT forms of tau impair memory-consolidating hippocampal function; this must be considered when interpreting tau…”
- Neurotoxicity of amyloid β-protein: synaptic and network dysfunction. (2012, background): “Such hypothetical tau functions could play a critical role in the pathogenesis of dementia and are not inconsistent with evidence that pathogenic tau aggregates cause neurodegeneration in AD and other tauopathies (Hoover et al. 2010; Zempel et al. 2010).”
- Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. (2012, neutral): “2010), as well as on the disruption of glutamate receptor trafficking and recycling (Hoover et al. 2010).”
- Tau protein liquid–liquid phase separation can initiate tau aggregation (2018, neutral): “However, the observed FRAP recovery of the GFP-tau droplets excludes the possibility that the observed spherical droplets resemble large tau aggregates previously reported for mutant tau expressed in neurons (Hoover et al , 2010).”
- The neuropathological diagnosis of Alzheimer’s disease (2019, background): “dysfunction may be complemented by the arrival of hyperphosphorylated tau in dendritic spines and concomitant impaired synaptic transmission [98].”
- Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019, neutral): “Hyperphosphorylated tau is also redirected from the axonal compartment to the somatodendritic compartment where it can impair synaptic function by inhibiting glutamate receptor trafficking or synaptic anchoring (Hoover et al., 2010).”