Altered phosphorylation but no neurodegeneration in a mouse model of tau hyperphosphorylation

Hundelt, Monika; Fath, Thomas; Selle, K.; Oesterwind, K.; Jordán, Joaquı́n; Schultz, Christian; Götz, Jürgen; Engelhardt, Jakob von; Monyer, Hannah; Lewejohann, Lars; Sachser, Norbert; Bakota, Lidia; Brandt, Roland

doi:10.1016/j.neurobiolaging.2009.06.007

Cited by 23 publications

(21 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a transgenic Caenorhabditis elegans model, PHP-tau induced a developmental defect (Brandt et al. , 2009), and we observed altered tau phosphorylation at additional, nonmodified sites in transgenic mice (Hundelt et al. , 2011).…”

Section: Resultsmentioning

confidence: 50%

Presence of a carboxy-terminal pseudorepeat and disease-like pseudohyperphosphorylation critically influence tau’s interaction with microtubules in axon-like processes

Niewidok

Igaev

Sündermann

et al. 2016

MBoC

View full text Add to dashboard Cite

show abstract

Section: Resultsmentioning

confidence: 50%

Presence of a carboxy-terminal pseudorepeat and disease-like pseudohyperphosphorylation critically influence tau’s interaction with microtubules in axon-like processes

Niewidok

Igaev

Sündermann

et al. 2016

MBoC

View full text Add to dashboard Cite

show abstract

“…The choice was motivated by two reasons: (1) EGFP-tau - compared to EGFP, which shows due to its small size also some nuclear localization - is completely cytosolic and more efficiently labels neurons with all protrusions, (2) we have previously shown that exogenous human tau expression does not interfere with spine density or morphology in hippocampal slices (Shahani et al, 2006; Tackenberg and Brandt, 2009). Furthermore, we and others have shown that transgenic expression of wild type human tau also has no effect on spine density in the hippocampus of mice (Dickstein et al, 2010; Hundelt et al, 2011), although the mice exhibited a shift from mushroom spines to thin spines as a function of human tau aggregation (Dickstein et al, 2010). Very recently it has been confirmed that tau is not required for spine loss in primary neurons (Umeda et al, 2015).…”

Section: Resultsmentioning

confidence: 86%

“…Brains were stored in PBS at 4°C. For rapid Golgi-staining, brains were stained according to (Hundelt et al, 2011). In short, PFA-fixed brains were incubated in 2.5% (w/v) K 2 Cr 2 O 7 at 34°C for 3 days.…”

Section: Methodsmentioning

confidence: 99%

Aβ-mediated spine changes in the hippocampus are microtubule-dependent and can be reversed by a subnanomolar concentration of the microtubule-stabilizing agent epothilone D

et al. 2016

View full text Add to dashboard Cite

Dendritic spines represent the major postsynaptic input of excitatory synapses. Loss of spines and changes in their morphology correlate with cognitive impairment in Alzheimer’s disease (AD) and are thought to occur early during pathology. Therapeutic intervention at a preclinical stage of AD to modify spine changes might thus be warranted. To follow the development and to potentially interfere with spine changes over time, we established a long term ex vivo model from organotypic cultures of the hippocampus from APP transgenic and control mice. The cultures exhibit spine loss in principal hippocampal neurons, which closely resembles the changes occurring in vivo, and spine morphology progressively changes from mushroom-shaped to stubby. We demonstrate that spine changes are completely reversed within few days after blocking amyloid-β (Aβ) production with the gamma-secretase inhibitor DAPT. We show that the microtubule disrupting drug nocodazole leads to spine loss similar to Aβ expressing cultures and suppresses DAPT-mediated spine recovery in slices from APP transgenic mice. Finally, we report that epothilone D (EpoD) at a subnanomolar concentration, which slightly stabilizes microtubules in model neurons, completely reverses Aβ-induced spine loss and increases thin spine density. Taken together the data indicate that Aβ causes spine changes by microtubule destabilization and that spine recovery requires microtubule polymerization. Moreover, our results suggest that a low, subtoxic concentration of EpoD is sufficient to reduce spine loss during the preclinical stage of AD.

show abstract

“…In the former study, 14 serine and threonine residues were simultaneously changed to either alanine (termed AP), or glutamate (termed E14), resulting in an approximately four-fold increase in the spine localization of E14 Tau and a four-fold decrease in the localization of AP compared to wild-type Tau. In our study, we refrained from mutating 14 sites simultaneously and rather mutated individual sites, although we had previously generated transgenic mice expressing E10-mutated Tau [18]. Our approach of mutating single phosphoepitopes allowed us to demonstrate that not all sites mediate spine localization equally (AT180, 12E8, and PHF1 do, whereas S422 does not), and to show that introducing a single pseudophosphorylation epitope is sufficient to target Tau efficiently to the spine.…”

Section: Discussionmentioning

confidence: 99%

Pseudophosphorylation of Tau at distinct epitopes or the presence of the P301L mutation targets the microtubule-associated protein Tau to dendritic spines

Xia

Götz

2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

View full text Add to dashboard Cite

Alzheimer's disease is characterized by the accumulation of amyloid-β (Aβ) and Tau in the brain. In mature neurons, Tau is concentrated in the axon and found at lower levels in the dendrite where it is required for targeting Fyn to the spines. Here Fyn mediates Aβ toxicity, which is vastly abrogated when Tau is either deleted or a truncated form of Tau (Tau(1-255)) is co-expressed. Interestingly, MAP2, a microtubule-binding protein with mainly dendritic localization that shares Fyn-binding motifs with Tau, does not mediate Aβ's synaptic toxicity in the absence of Tau. Here we show in hippocampal neurons that endogenous Tau enters the entire spine, albeit at low levels, whereas MAP2 only enters its neck or is restricted to the dendritic shaft. Based on an extensive mutagenesis study, we also reveal that the spine localization of Tau is facilitated by deletion of the microtubule-binding repeat domain. When distinct phosphorylation sites (AT180-T231/S235, 12E8-S262/S356, PHF1-S396/S404) were pseudophosphorylated (with glutamic acid, using alanine replacements as controls), Tau targeting to spines was markedly increased, whereas the pseudophosphorylation of the late phospho-epitope S422 had no effect. In determining the role physiological Fyn has in the spine localization of Tau, we found that neither were endogenous Tau levels reduced in Fyn knockout compared with wild-type synaptosomal brain fractions nor was the spine localization of over-expressed pseudophosphorylated or P301L Tau. This demonstrates that although Fyn targeting to the spine is Tau dependent, elevated levels of phosphorylated Tau or P301L Tau can enter the spine in a Fyn-independent manner.

show abstract

Altered phosphorylation but no neurodegeneration in a mouse model of tau hyperphosphorylation

Cited by 23 publications

References 61 publications

Presence of a carboxy-terminal pseudorepeat and disease-like pseudohyperphosphorylation critically influence tau’s interaction with microtubules in axon-like processes

Presence of a carboxy-terminal pseudorepeat and disease-like pseudohyperphosphorylation critically influence tau’s interaction with microtubules in axon-like processes

Aβ-mediated spine changes in the hippocampus are microtubule-dependent and can be reversed by a subnanomolar concentration of the microtubule-stabilizing agent epothilone D

Pseudophosphorylation of Tau at distinct epitopes or the presence of the P301L mutation targets the microtubule-associated protein Tau to dendritic spines

Contact Info

Product

Resources

About