Age-dependent axonal transport and locomotor changes and tau hypophosphorylation in a “P301L” tau knockin mouse

Gilley, Jonathan; Seereeram, Anjan; Ando, Kunie; Mosely, Suzanne; Andrews, Simon; Kerschensteiner, Martin; Misgeld, Thomas; Brion, Jean Pierre; Anderton, Brian H.; Hanger, Diane P.; Coleman, Michael P.

doi:10.1016/j.neurobiolaging.2011.02.014

Cited by 79 publications

(84 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To investigate whether the reduction of mitochondrial density is a consequence of reduced transport, we directly measured the flux of fluorescently labeled mitochondria in intercostal nerves in triangularis sterni nervemuscle explants (18) and in isolated tibialis nerves (the nerve that innervates the gastrocnemius muscle; ref. 19). Indeed, in both preparations, anterograde and retrograde transport flux of mitochondria were reduced in SOD G93A , Thy1-MitoCFP motor axons at an advanced stage of the disease (4 mo after birth; Fig.…”

Section: Resultsmentioning

confidence: 81%

Axonal transport deficits and degeneration can evolve independently in mouse models of amyotrophic lateral sclerosis

Marinković

Reuter

Brill

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Axonal transport deficits have been reported in many neurodegenerative conditions and are widely assumed to be an immediate causative step of axon and synapse loss. By imaging changes in axonal morphology and organelle transport over time in several animal models of amyotrophic lateral sclerosis (ALS), we now find that deficits in axonal transport of organelles (mitochondria, endosomes) and axon degeneration can evolve independently. This conclusion rests on the following results: (i) Axons can survive despite long-lasting transport deficits: In the SOD G93A model of ALS, transport deficits are detected soon after birth, months before the onset of axon degeneration. (ii) Transport deficits are not necessary for axon degeneration: In the SOD G85R model of ALS, motor axons degenerate, but transport is unaffected. (iii) Axon transport deficits are not sufficient to cause immediate degeneration: In mice that overexpress wild-type superoxide dismutase-1 (SOD WT ), axons show chronic transport deficits, but survive. These data suggest that disturbances of organelle transport are not a necessary step in the emergence of motor neuron degeneration.

show abstract

Section: Resultsmentioning

confidence: 81%

Axonal transport deficits and degeneration can evolve independently in mouse models of amyotrophic lateral sclerosis

Marinković

Reuter

Brill

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…We recently addressed these issues using a novel knockin approach [25]. We engineered mice with a mutation in the endogenous Mapt gene that is homologous with the common P301L MAPT mutation found in patients with FTDP-17T (frontotemporal dementia with parkinsonism linked to tau mutations on chromosome 17).…”

Section: A Knockin Model For Ftdp-17tmentioning

confidence: 99%

Modelling early responses to neurodegenerative mutations in mice

Gilley

Adalbert

Coleman

2011

Biochemical Society Transactions

Self Cite

View full text Add to dashboard Cite

Considering the many differences between mice and humans, it is perhaps surprising how well mice model late-onset human neurodegenerative disease. Models of Alzheimer's disease, frontotemporal dementia, Parkinson's disease and Huntington's disease show some striking similarities to the corresponding human pathologies in terms of axonal transport disruption, protein aggregation, synapse loss and some behavioural phenotypes. However, there are also major differences. To extrapolate from mouse models to human disease, we need to understand how these differences relate to intrinsic limitations of the mouse system and to the effects of transgene overexpression. In the present paper, we use examples from an amyloid-overexpression model and a mutant-tau-knockin model to illustrate what we learn from each type of approach and what the limitations are. Finally, we discuss the further contributions that knockin and similar approaches can make to understanding pathogenesis and how best to model disorders of aging in a short-lived mammal.

show abstract

“…Although the APP mutant knock-ins were able to successfully recreate the typical Aβ pathology previously reported, the P301L knockin mice failed to develop end-stage NFT pathology [102,103]. As we enter a newage of gene editing tools it is hopeful to predict an emergence of more elegant AD mouse models, better engineered to address current criticisms of transgenic models [104].…”

Section: Genetic Modelsmentioning

confidence: 96%

“…Therefore, recently knock-in approaches have been pursued to insert familial human mutations into the murine APP locus and P301L mutation of tau into the murine MAPT locus [102,103]. Although the APP mutant knock-ins were able to successfully recreate the typical Aβ pathology previously reported, the P301L knockin mice failed to develop end-stage NFT pathology [102,103].…”

Section: Genetic Modelsmentioning

confidence: 99%

Investigating in vivo the principles governing the spread of tau phosphorylation and amyloid-beta excitotoxicity

Baker¹

View full text Add to dashboard Cite

Alzheimers disease (AD) is a devastating neurodegenerative disease which presents clinically with progressive loss of memory, executive function and cognitive abilities.Traditionally AD is diagnosed post-mortem by presence of two hallmark lesions, extracellular plaques comprised of amyloid-beta (Aβ) and intracellular neurofibrillary tangles (NFTs) containing hyperphosphorylated microtubule-associated protein tau.The current available therapies for the treatment of AD only provide mild symptomatic relief and cannot halt the ongoing disease progression. Therefore, the research presented focuses on the mechanisms underlying disease propagation specifically that of hyperphosphorylated tau pathology, and understanding potential disease modifying therapeutics targeting known mechanisms, specifically TatNR2b9c peptide induced neuroprotection against Aβ induced excitotoxicity.Current approaches to investigate tau propagation have utilised tau transgenic recipient mice, mutant tagged tau constructs and whole brain lysates to establish tau seeding and spreading in vitro. To circumvent caveats of this technique and progress our understanding of tau seeding events we proposed a two-pronged approach.Firstly, we created an endogenous model of tau hyperphosphorylation by inhibiting tau dephosphorylation with the unilateral injection of the inhibitor okadaic acid. By keeping the concentration and volume low we were able to show by ELISA that the spread of the inhibitor could be restricted, and this single exposure was sufficient to induce tau hyperphosphorylation, increases in insolubilty and thioflavin-S NFT-Like immunoreactivity at both the injection site and anatomically distinct non-exposed brain regions. Secondly, we injected exosome and large extracellular vesicle fractions derived from tau transgenic mice into human tau expressing mice and compared there seeding ability to brain lysate. Under our experiment parameters we did not observe any NFT positivity and could not recreate previous seeding using brain lysates. Interestingly, both brain lysates and exosomes increased AT8 phosphorylation and oligomeric tau deposition in the hippocampus, whereas large extracellular vesicles did not.To address whether the Tat-NR2b9c peptide can provide long-term protection against Aβ induced excitotoxicity we treated mutant amyloid precursor protein 3 transgenic mice at both young and old age and investigated amyloid levels and NMDA receptor subunit expression in synaptic and extrasynaptic zones.Unfortunately, lack of a robust behavioural deficit in our aged APP23 cohort prevented us from performing a therapeutic intervention study. However, biochemical analysis of aged Tat-NR2b9c revealed a similar effect on synaptic redistribution of NMDA receptor subunits as that observed in young treated mice, indicating that the peptide may be a viable therapeutic prospect for late stage intervention in AD.This work demonstrates that mechanisms underlying tau spreading may also be studied by using endogenous mouse tau models. An avenue whic...

show abstract

Age-dependent axonal transport and locomotor changes and tau hypophosphorylation in a “P301L” tau knockin mouse

Cited by 79 publications

References 79 publications

Axonal transport deficits and degeneration can evolve independently in mouse models of amyotrophic lateral sclerosis

Axonal transport deficits and degeneration can evolve independently in mouse models of amyotrophic lateral sclerosis

Modelling early responses to neurodegenerative mutations in mice

Investigating in vivo the principles governing the spread of tau phosphorylation and amyloid-beta excitotoxicity

Contact Info

Product

Resources

About