Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model

Zhang, Bin; Maiti, Arpita; Shively, Sharon; Lakhani, Fara; McDonald-Jones, Gaye; Bruce, Jennifer; Lee, Edward B.; Xie, Sharon X.; Joyce, Sonali; Li, Chi; Toleikis, Philip M.; Lee, Virginia M.‐Y.; Trojanowski, John Q.

doi:10.1073/pnas.0406361102

Cited by 371 publications

(320 citation statements)

References 24 publications

Supporting

Mentioning

312

Contrasting

Unclassified

Order By: Relevance

“…While other mechanisms cannot be excluded, the aforementioned sciatic nerve deficits may critically contribute to motor deficits found in old Tau−/− as fine‐tuning of myelin sheath thickness and formation is important for maintenance and proper function of motor fibers. In addition, while no amplitude differences in muscle action potentials of Tau−/− were found, further studies are needed to clarify the impact of loss of Tau on neuromuscular junction by aging as Tau‐related pathology in motor neurons has been shown to have neuromuscular junction malfunction and motor deficits in AD Tg models (Zhang et al ., 2005; Ubhi et al ., 2007). …”

Section: Discussionmentioning

confidence: 99%

Absence of Tau triggers age‐dependent sciatic nerve morphofunctional deficits and motor impairment

Lopes

Pinto

et al. 2016

Aging Cell

View full text Add to dashboard Cite

SummaryDementia is the cardinal feature of Alzheimer's disease (AD), yet the clinical symptoms of this disorder also include a marked loss of motor function. Tau abnormal hyperphosphorylation and malfunction are well‐established key events in AD neuropathology but the impact of the loss of normal Tau function in neuronal degeneration and subsequent behavioral deficits is still debated. While Tau reduction has been increasingly suggested as therapeutic strategy against neurodegeneration, particularly in AD, there is controversial evidence about whether loss of Tau progressively impacts on motor function arguing about damage of CNS motor components. Using a variety of motor‐related tests, we herein provide evidence of an age‐dependent motor impairment in Tau−/− animals that is accompanied by ultrastructural and functional impairments of the efferent fibers that convey motor‐related information. Specifically, we show that the sciatic nerve of old (17–22‐months) Tau−/− mice displays increased degenerating myelinated fibers and diminished conduction properties, as compared to age‐matched wild‐type (Tau+/+) littermates and younger (4–6 months) Tau−/− and Tau+/+ mice. In addition, the sciatic nerves of Tau−/− mice exhibit a progressive hypomyelination (assessed by g‐ratio) specifically affecting large‐diameter, motor‐related axons in old animals. These findings suggest that loss of Tau protein may progressively impact on peripheral motor system.

show abstract

Section: Discussionmentioning

confidence: 99%

Absence of Tau triggers age‐dependent sciatic nerve morphofunctional deficits and motor impairment

Lopes

Pinto

et al. 2016

Aging Cell

View full text Add to dashboard Cite

show abstract

“…221 Weekly taxol treatment of tau transgenic mice over 12 weeks restored fast anterograde transport, increased the number of axonal microtubules, and diminished motor deficits. 222 Other microtubule-stabilizing approaches are reviewed by Michelis et al 223,224 The neuronal tubulin-preferring agent NAP was reported to display less side effects than the non-cell-typespecific taxol, which inhibits cell mitosis in general. 225 The octapeptide NAPVSIPQ (NAP) has a preference for neuronal tubulin and crosses the BBB readily when administered intranasally.…”

Section: Microtubule-stabilizing Drugsmentioning

confidence: 99%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

View full text Add to dashboard Cite

Summary:Neurofibrillary tangles are a characteristic hallmark of Alzheimer's and other neurodegenerative diseases, such as Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). These diseases are summarized as tauopathies, because neurofibrillary tangles are composed of intracellular aggregates of the microtubule-associated protein tau. The molecular mechanisms of tau-mediated neurotoxicity are not well understood; however, pathologic hyperphosphorylation and aggregation of tau play a central role in neurodegeneration and neuronal dysfunction. The present review, therefore, focuses on therapeutic approaches that aim to inhibit tau phosphorylation and aggregation or to dissolve preexisting tau aggregates. Further experimental therapy strategies include the enhancement of tau clearance by activation of proteolytic, proteasomal, or autophagosomal degradation pathways or anti-tau directed immunotherapy. Hyperphosphorylated tau does not bind microtubules, leading to microtubule instability and transport impairment. Pharmacological stabilization of microtubule networks might counteract this effect. In several tauopathies there is a shift toward four-repeat tau isoforms, and interference with the splicing machinery to decrease four-repeat splicing might be another therapeutic option.

show abstract

“…This adversely affects cell function because the shortening and lengthening of microtubules (dynamic instability) is necessary for their function as a mechanism to transport other cellular components (e.g., the mitosis where microtubules position the chromosomes during their replication and subsequent separation into the two daughter-cell nuclei). Despite these adverse effects, low doses of paclitaxel may have a therapeutic benefit in human tauopathies by offsetting the loss of normal tau functions that result from its hyperphosphorylation and sequestration into tangles (Zhang et al 2005). …”

Section: Induction Of Abnormal Phosphorylation Of Tau By Paclitaxel Amentioning

confidence: 99%

Effects of Cell Cycle Inhibitors on Tau Phosphorylation in N2aTau3R Cells

2008

View full text Add to dashboard Cite

Neurofibrillary tangles are one of the pathologic hallmarks of Alzheimer's disease (AD). They are composed of paired helical filaments (PHF) containing hyperphosphorylated forms of tau. Hyperphosphorylation of certain tau sites favors its dissociation from the microtubules (MT), interfering with axonal transport and compromising the function and viability of neurons. Reappearance of cell cycle proteins have been reported in neurons exhibiting tau aggregation, suggesting that an aberrant cell cycle occurs before neurons die. Cell cycle suppression in neurons is crucial to survival, thus prevention of progression through the cell cycle may offer a therapeutic approach. Using a neuroblastoma cell line overexpressing 3-repeat (3R) tau, we investigated the effects of cell cycle inhibitors on tau phosphorylation. G2/M phase inhibitors did not alter phosphorylation of tau at Ser-202 and Ser-396/404 at the lower doses, but did at higher doses. Ser-202 and Ser-396/404 are phosphorylation sites of early and late neurofibrillary tangles, respectively, in AD. Cisplatin, a G1 phase inhibitor, did not phosphorylate tau. Cyclophosphamide and phosphoramide mustard, DNA cross-linking agents, decreased tau phosphorylation at Ser-396/404 site, but increased phosphorylation at Ser-202. These studies demonstrate that the G2/M blockers have a dose-dependent effect on tau phosphorylation. This seems to be a consequence of both the disruption of MT-organization and MT-dynamics when doses are higher, but only a disruption of MT-dynamics with lower doses. These results are also in agreement with the lack of phosphorylation seen for cisplatin, another inhibitor that produces disruption of the MT-dynamics.

show abstract

Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model

Cited by 371 publications

References 24 publications

Absence of Tau triggers age‐dependent sciatic nerve morphofunctional deficits and motor impairment

Absence of Tau triggers age‐dependent sciatic nerve morphofunctional deficits and motor impairment

Tau-Based Treatment Strategies in Neurodegenerative Diseases

Effects of Cell Cycle Inhibitors on Tau Phosphorylation in N2aTau3R Cells

Contact Info

Product

Resources

About