Abstract
Tau is a major component of the neurofibrillary tangles (NFT) that represent a pathological hallmark of Alzheimer's disease (AD). Although generally considered an axonal protein, Tau is found in the somato-dendritic compartment of degenerating neurons and this redistribution is thought to be a trigger of neurodegeneration in AD. Here, we show the presence of tau mRNA in a dendritic ribonucleoprotein (RNP) complex that includes Ca2+-calmodulin dependent protein kinase (CaMK)IIα mRNA and that is translated locally in response to glutamate stimulation. Further, we show that Tau mRNA is a component of mRNP granules that contain RNA-binding proteins, and that it interacts with Myosin Va, a postsynaptic motor protein; these findings suggest that tau mRNA is transported into dendritic spines. We also report that tau mRNA localized in the somato-dendritic component of primary hippocampal cells and that a sub-toxic concentration of glutamate enhances local translation and hyperphosphorylation of tau, effects that are blocked by the gluatamatergic antagonists MK801 and NBQX. These data thus demonstrate that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-d-aspartate (NMDA) stimulation redistributes tau to the somato-dendritic region of neurons where it may trigger neurodegeneration.
Highlights
Intracellular inclusions of hyperphosphorylated tau protein and extracellular deposits of amyloid β (Aβ) are prominent neuropathological features in Alzheimer disease brains
Whereas RNP granules recovered by immunopreciptation with antiStaufen 1 (Fig. 1a) and anti-Fragile X mental retardation protein (FMRP) (Fig. 1b) from the hippocampi of wild type (WT) and tau knockout (KO) mice expressed CamKIIα and tau mRNA, immunoprecipitates from tau KO animals only contained CamKIIα mRNA; importantly, Math2 mRNA, whose expression is restricted to the cytoplasm, did not co-immunpreicipate with the RNPs in preparations from WT and tau KO mice (Fig. 1a, b), indicating that tau is bound to Staufen1- and FMRP-containing mRNP in dendrites
Immunoprecipitation of hippocampal synaptosomes demonstrated that BC1 RNA and the mRNAs encoding CaMKIIα and tau are associated with Staufen1, FMRP and myosin Va (Supplemental Fig. 2b)
Summary
Intracellular inclusions of hyperphosphorylated tau protein (neurofibrillary tangles, NFT) and extracellular deposits of amyloid β (Aβ) are prominent neuropathological features in Alzheimer disease brains. In the AD brain, tau is hyperphosphorylated and forms fibrils that appear as neuropil threads in dendrites and as NFTs in the somatodendritic compartment and axons. NFT formation is preceded by a pre-tangle stage where non-fibrillar and hyperphosphorylated tau accumulates in the soma and dendrites of neurons (Uchihara et al, 2001; Götz et al, 1995).
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