Synergistic effects of amyloid-beta and wild-type human tau on dendritic spine loss in a floxed double transgenic model of Alzheimer's disease

Chabrier, Meredith A.; Cheng, David; Castello, Nicholas A.; Green, Kim N.; LaFerla, Frank M.

doi:10.1016/j.nbd.2014.01.007

Cited by 94 publications

(96 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Strong effects of mutant Tau on spines have been demonstrated in several studies. For example, expression of mutant Tau in vivo has been shown to affect spine morphology and eventually cause spine loss [22], a phenotype that is augmented by Aβ [4,6]. In P301S Tau mice, the fraction of thin spines was found to be strongly reduced, whereas that of mushroom spines was found to be increased compared to controls [16].…”

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

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

show abstract

“…Strong effects of mutant Tau on spines have been demonstrated in several studies. For example, expression of mutant Tau in vivo has been shown to affect spine morphology and eventually cause spine loss [89], a phenotype that is augmented by Aβ [90,91]. In P301S Tau mice, the fraction of thin spines was found to be strongly reduced, whereas that of mushroom spines was found to be increased compared to controls [85].…”

Section: Discussionmentioning

confidence: 99%

The molecular mechanism of the Tau-Fyn interaction and dendritic targeting in neurons

Xia¹

View full text Add to dashboard Cite

Alzheimer's disease (AD) is the most common form of neurodegenerative disorder that progresses with aging. The AD brain is characterized by a massive loss of neurons and synapses. Two key hallmarks of AD are the aggregation of the amyloid-β (Aβ) peptide as plaques and of the microtubule-associated protein Tau as neurofibrillary tangles. Under physiological conditions, Tau is mainly localized to the axon of neurons, with low levels of expression found in dendrites and spines. Under disease conditions, Tau is hyperphosphorylated and accumulates in the somatodendritic domain of neurons including spines. Recent data suggest that dendritic spine-targeted Tau disrupts synaptic function and causes synaptic loss long before neurofibrillary tangle formation and neuronal loss occurs.Fyn is a non-receptor tyrosine kinase that mainly targets to the postsynaptic membrane in spines. Fyn interacts with and phosphorylates Tau and this interaction has a critical role in mediating Aβ toxicity. Understanding how Tau and Fyn are targeted to the dendritic spine and how their trafficking and interaction is regulated under both physiological and pathological conditions is critical for understanding how AD is initiated in the synapse and for developing novel therapeutic approaches to delay, halt or treat AD.Fyn phosphorylates Tau mainly at Tyr18; however, it is unclear how tyrosine phosphorylation of Tau by Fyn affects serine/ threonine phosphorylation. In the first part of my thesis, I have generated a transgenic animal model that expresses constitutively active Fyn and studied the functional consequence of Fyn activation, especially for Tau. We found that FynCA animals showed premature lethality and hyperactive phenotypes reflecting the synaptic over-excitation by Fyn as expected. A biochemical analysis of isolated synaptosomes revealed increased levels of the NMDA receptor subunit NR2b phosphorylated at residue Y1472, and of Tau phosphorylated at the 12E8 phosphoepitope S262/S356. Besides, Tau phosphorylation at the AT8 epitope S202/T205 was strongly increased in FynCA mice as revealed by both immunohistochemistry and Western blot analysis. Our results indicate that an increased tyrosine kinase activity of Fyn has a role in serine/threonine-directed phosphorylation of Tau, which may contribute to the tauopathy in AD. 3 Under physiological conditions, low levels of Tau are targeted to dendritic spines in a process that is regulated by synaptic activity and Aβ levels. It has also been reported that hyperphosphorylated Tau mislocalizes into the spine, although it is not clear what kind of phosphorylation is required. In order to understand how Tau enters the spines and the role of Fyn in dendritic spine targeting of Tau, we performed an extensive mutagenesis study by overexpressing different mutant forms of Tau in cultured wildtype or FynKO neurons.Our results revealed that the spine localization of Tau is facilitated by deletion of the microtubule-binding repeat domain. Distinct pseudophosphorylation at AD related sites AT180(...

show abstract

“…Misfolded proteins can accumulate or aggregate and form fibrils, like the neurofilaments which can be found in the brain, heart or spleen of patients [47,205]. Their accumulation is associated with a number of diseases such as Alzheimer's [31,39,75], type-II diabetes [47,205] and Parkinson's disease [77,120,141,182,213]. …”

Section: Protein Foldingmentioning

confidence: 99%

“…Shifting attention to the contribution of the conservative potential to the equation of motion, 31) one observes that the last term is parallel to q and, hence, will be eliminated by the constraint. Replacing Φ by ln g q we observe that also in this case the last term is proportional to q, while for the other term, using g q as derived in Appendix 3.6.1, it follows that…”

Section: Simplification Of Termsmentioning

confidence: 99%

See 1 more Smart Citation

Chameleon behaviour of a-synuclein : brownian dynamics simulations of protein aggregation

Ilie

View full text Add to dashboard Cite

Synergistic effects of amyloid-beta and wild-type human tau on dendritic spine loss in a floxed double transgenic model of Alzheimer's disease

Cited by 94 publications

References 37 publications

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

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

The molecular mechanism of the Tau-Fyn interaction and dendritic targeting in neurons

Chameleon behaviour of a-synuclein : brownian dynamics simulations of protein aggregation

Contact Info

Product

Resources

About