Changes in TDP-43 expression in development, aging, and in the neurofilament light protein knockout mouse

Liu, Yao; Atkinson, Rachel A.K.; Fernández-Martos, Carmen M.; Kirkcaldie, Matthew; Cui, Hao; Vickers, James C.; King, Anna E.

doi:10.1016/j.neurobiolaging.2014.10.001

Cited by 18 publications

(13 citation statements)

References 58 publications

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“…Postnatal loss of TDP-43 is lethal in mice [64]; in vitro, depletion has been shown to inhibit neurite outgrowth and survival of differentiated N2A cells [65], and to increase the number of dendritic spines in hippocampal neurons [66]. Intriguingly, TDP-43 is highly expressed in the embryonic cortex, but is rapidly downregulated at the end of corticogenesis [67]. It should thus be interesting in future studies to investigate TDP-43 as a potential interactor of mammalian Akirin2 and regulator of corticogenesis.…”

Section: Discussionmentioning

confidence: 99%

Akirin2 is essential for the formation of the cerebral cortex

et al. 2016

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BackgroundThe proper spatial and temporal regulation of dorsal telencephalic progenitor behavior is a prerequisite for the formation of the highly-organized, six-layered cerebral cortex. Premature differentiation of cells, disruption of cell cycle timing, excessive apoptosis, and/or incorrect neuronal migration signals can have devastating effects, resulting in a number of neurodevelopmental disorders involving microcephaly and/or lissencephaly. Though genes encoding many key players in cortical development have been identified, our understanding remains incomplete. We show that the gene encoding Akirin2, a small nuclear protein, is expressed in the embryonic telencephalon. Converging evidence indicates that Akirin2 acts as a bridge between transcription factors (including Twist and NF-κB proteins) and the BAF (SWI/SNF) chromatin remodeling machinery to regulate patterns of gene expression. Constitutive knockout of Akirin2 is early embryonic lethal in mice, while restricted loss in B cells led to disrupted proliferation and cell survival.MethodsWe generated cortex-restricted Akirin2 knockouts by crossing mice harboring a floxed Akirin2 allele with the Emx1-Cre transgenic line and assessed the resulting embryos using in situ hybridization, EdU labeling, and immunohistochemistry.ResultsThe vast majority of Akirin2 mutants do not survive past birth, and exhibit extreme microcephaly, with little dorsal telencephalic tissue and no recognizable cortex. This is primarily due to massive cell death of early cortical progenitors, which begins at embryonic day (E)10, shortly after Emx1-Cre is active. Immunostaining and cell cycle analysis using EdU labeling indicate that Akirin2-null progenitors fail to proliferate normally, produce fewer neurons, and undergo extensive apoptosis. All of the neurons that are generated in Akirin2 mutants also undergo apoptosis by E12. In situ hybridization for Wnt3a and Wnt-responsive genes suggest defective formation and/or function of the cortical hem in Akirin2 null mice. Furthermore, the apical ventricular surface becomes disrupted, and Sox2-positive progenitors are found to “spill” into the lateral ventricle.ConclusionsOur data demonstrate a previously-unsuspected role for Akirin2 in early cortical development and, given its known nuclear roles, suggest that it may act to regulate gene expression patterns critical for early progenitor cell behavior and cortical neuron production.Electronic supplementary materialThe online version of this article (doi:10.1186/s13064-016-0076-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Akirin2 is essential for the formation of the cerebral cortex

et al. 2016

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“…Denatured protein samples (20 μg) from each group were electrophoresed into Bolt Bis-Tris Plus gels (Invitrogen, Camarillo, CA, USA), transferred to PVDF membranes (BioRad) and incubated with primary antibodies (rabbit anti-synaptophysin [SYN, 1:1000; Millipore], mouse anti-PSD-95 [1:1000; Abcam], rabbit anti-vGLUT1 [1:1000; Synaptic Systems], mouse anti-GAD65 [1:1000; Abcam] and mouse anti-GAD67 [1:1000; Millipore], anti-GFAP [1:1000; Dako], and anti-Iba1 [1:1000; Synaptic Systems]) overnight. Subsequently, a corresponding antirabbit or antimouse horseradish peroxidase–conjugated secondary antibody (1:7000; Dako) was used, as described previously [40] . β-Actin (1:7000, Sigma) was used as a loading control, and band intensity was measured as the integrated intensity using ImageJ software (v1.4; NIH).…”

Section: Methodsmentioning

confidence: 99%

Combination treatment with leptin and pioglitazone in a mouse model of Alzheimer's disease

Fernández-Martos

Atkinson

Chuah

et al. 2016

A&D Transl Res & Clin Interv

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IntroductionCombination therapy approaches may be necessary to address the many facets of pathologic change in the brain in Alzheimer's disease (AD). The drugs leptin and pioglitazone have previously been shown individually to have neuroprotective and anti-inflammatory actions, respectively, in animal models.MethodsWe studied the impact of combined leptin and pioglitazone treatment in 6-month-old APP/PS1 (APPswe/PSEN1dE9) transgenic AD mouse model.ResultsWe report that an acute 2-week treatment with combined leptin and pioglitazone resulted in a reduction of spatial memory deficits (Y maze) and brain β-amyloid levels (soluble β-amyloid and amyloid plaque burden) relative to vehicle-treated animals. Combination treatment was also associated with amelioration in plaque-associated neuritic pathology and synapse loss, and also a significantly reduced neocortical glial response.DiscussionCombination therapy with leptin and pioglitazone ameliorates pathologic changes in APP/PS1 mice and may represent a potential treatment approach for AD.

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“…At 9 months of age, mice were terminally anesthetized (sodium pentobarbitone, 110 mg/kg IP) and transcardially perfused (0.01 M PBS), the neocortex was then quickly removed and frozen in liquid nitrogen. Samples were homogenized in RIPA buffer (Sigma-Aldrich) containing a proteinase inhibitor cocktail (Roche) as previously [ 59 ]. Denatured proteins samples (20 μg) were electrophoresed into Bolt® Bis-Tris Plus gels (Invitrogen), transferred to PVDF membranes (BioRad), and incubated overnight in primary antibody solution at 4 °C.…”

Section: Methodsmentioning

confidence: 99%

Repeat propofol anesthesia does not exacerbate plaque deposition or synapse loss in APP/PS1 Alzheimer’s disease mice

et al. 2018

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BackgroundThere is increasing interest in whether anesthetic agents affect the risk or progression of Alzheimer’s disease (AD). To mitigate many of the methodological issues encountered in human retrospective cohort studies we have used a transgenic model of AD to investigate the effect of propofol on AD pathology.MethodsSix month-old amyloid precursor protein/presenilin 1 (APP/PS1) transgenic AD mice and control mice were exposed to 3 doses of propofol (200 mg/kg) or vehicle, delivered at monthly intervals.ResultsThere was no difference in the extent of β-amyloid (Aβ) immunolabeled plaque deposition in APP/PS1 mice in vehicle versus propofol treatment groups. We also detected no difference in plaque-associated synapse loss in APP/PS1 mice following repeat propofol exposure relative to vehicle. Western blotting indicated that there was no difference in post-synaptic density protein 95, synaptophysin or glutamic acid decarboxylase 65/67 expression in control or APP/PS1 mice subjected to repeat propofol treatment relative to vehicle.ConclusionsThese data suggest that repeat propofol anesthesia may not exacerbate plaque deposition or associated synapse loss in AD. Interestingly, this data also provides some of the first evidence suggesting that repeat propofol exposure in adult wild-type mice does not result in robust long-term alterations in the levels of key excitatory and inhibitory synaptic markers.Electronic supplementary materialThe online version of this article (10.1186/s12871-018-0509-5) contains supplementary material, which is available to authorized users.

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Changes in TDP-43 expression in development, aging, and in the neurofilament light protein knockout mouse

Cited by 18 publications

References 58 publications

Akirin2 is essential for the formation of the cerebral cortex

Akirin2 is essential for the formation of the cerebral cortex

Combination treatment with leptin and pioglitazone in a mouse model of Alzheimer's disease

Repeat propofol anesthesia does not exacerbate plaque deposition or synapse loss in APP/PS1 Alzheimer’s disease mice

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