Strain Background Influences Neurotoxicity and Behavioral Abnormalities in Mice Expressing the Tetracycline Transactivator

Han, Harry; Allen, Carolyn C.; Buchovecky, Christie; Yetman, Michael J.; Born, Heather A.; Marin, Miguel A.; Rodgers, Shaefali P.; Song, Bryan J.; Lu, Hui-Chen; Justice, Monica J.; Probst, Frank J.; Jankowsky, Joanna L.

doi:10.1523/jneurosci.0893-12.2012

Cited by 89 publications

(112 citation statements)

References 56 publications

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“…Neurotoxicity and behavioral deficits have previously been reported in the tTA single transgenic animals [57], [58]. Therefore, it is important to use the tTA genotype as a control in all behavioral tests.…”

Section: Discussionmentioning

confidence: 99%

Tau Overexpression Impacts a Neuroinflammation Gene Expression Network Perturbed in Alzheimer’s Disease

et al. 2014

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Filamentous inclusions of the microtubule-associated protein, tau, define a variety of neurodegenerative diseases known as tauopathies, including Alzheimer’s disease (AD). To better understand the role of tau-mediated effects on pathophysiology and global central nervous system function, we extensively characterized gene expression, pathology and behavior of the rTg4510 mouse model, which overexpresses a mutant form of human tau that causes Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We found that the most predominantly altered gene expression pathways in rTg4510 mice were in inflammatory processes. These results closely matched the causal immune function and microglial gene-regulatory network recently identified in AD. We identified additional gene expression changes by laser microdissecting specific regions of the hippocampus, which highlighted alterations in neuronal network activity. Expression of inflammatory genes and markers of neuronal activity changed as a function of age in rTg4510 mice and coincided with behavioral deficits. Inflammatory changes were tau-dependent, as they were reversed by suppression of the tau transgene. Our results suggest that the alterations in microglial phenotypes that appear to contribute to the pathogenesis of Alzheimer’s disease may be driven by tau dysfunction, in addition to the direct effects of beta-amyloid.

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Section: Discussionmentioning

confidence: 99%

Tau Overexpression Impacts a Neuroinflammation Gene Expression Network Perturbed in Alzheimer’s Disease

et al. 2014

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“…Since we did not observe a toxic effect by GFP expression itself, it is likely to be the effect of tTA or the combination of GFP and tTA expression in the same cells. Transgenic expression of tTA is cytotoxic in certain mouse strains, and this cytotoxicity can be exacerbated by concomitant transgenic expression of APP (Han, et al, 2012). Nonetheless, our AAV2/1-CD200-injected WT and APP mice did not exhibit a reduction in BrdU + or Dcx + cells in the DG, suggesting that CD200 expression can overcome any tTA-induced toxicity.…”

Section: Discussionmentioning

confidence: 99%

The anti-inflammatory glycoprotein, CD200, restores neurogenesis and enhances amyloid phagocytosis in a mouse model of Alzheimer's disease

Varnum

Kiyota

Ingraham

et al. 2015

Neurobiology of Aging

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Cluster of Differentiation-200 (CD200) is an anti-inflammatory glycoprotein expressed in neurons, T cells, and B cells, and its receptor is expressed on glia. Both Alzheimer’s disease (AD) patients and mouse models display age-related or amyloid-β peptide (Aβ)-induced reductions in CD200. The goal of this study was to determine if neuronal CD200 expression restores hippocampal neurogenesis and reduces Aβ in the APP mouse model. APP and wild-type mice were injected at 6 months of age with an adeno-associated virus expressing CD200 into the hippocampus, and sacrificed at 12 months. CD200 expression restored neural progenitor cell proliferation and differentiation in the subgranular and granular cell layers of the dentate gyrus and reduced diffuse but not thioflavin-S+ plaques in the hippocampus. In vitro studies demonstrated that CD200-stimulated microglia increased neural differentiation of neural stem cells and enhanced axon elongation and dendrite number. CD200 also enhanced Aβ uptake by microglia. These data indicate that CD200 is capable of enhancing microglia-mediated Aβ clearance and neural differentiation and has potential as a therapeutic for AD.

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“…Nonetheless, a huge majority of studies continues to use it, even though better and nontoxic proliferation markers are available. More subtle effects on neural stem cells may arise from drugs such as tamoxifen used to activate genes in conditional mutant mice [Chen et al, 2013] or from transgenic insertion of a tetracycline transactivator permitting activation of CNSspecific genes by means of ingesting tetracycline or doxycycline [Han et al, 2012]. Domestication There is clear evidence that wheel-running in wild mice species do not have the stimulatory effect as commonly observed in mouse studies.…”

Section: Toxicity and Side Effects Of Substances Assessing Andmentioning

confidence: 99%

Adult Neurogenesis in Mammals: Variations and Confusions

Lipp

Bonfanti

2016

Brain Behav Evol

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Mammalian adult neurogenesis has remained enigmatic. Two lines of research have emerged. One focuses on a potential repair mechanism in the human brain. The other aims at elucidating its functional role in the hippocampal formation, chiefly in cognitive processes; however, thus far it has been unsuccessful. Here, we try to recognize the sources of errors and conceptual confusion in comparative studies and neurobehavioral approaches with a focus on mice. Evolutionarily, mammalian adult neurogenesis appears as protracted juvenile neurogenesis originating from precursor cells in the secondary proliferation zones, from where newly formed cells migrate to target regions in the forebrain. This late developmental process is downregulated differentially in various brain structures depending on species and age. Adult neurogenesis declines substantially during early adulthood and persists at low levels into senescence. Short-lasting episodes in proliferation or reduction of adult neurogenesis may reflect a multitude of factors, and have been studied chiefly in mice and rats. Comparative studies face both species-specific variations in staining and technical abilities of laboratories, lacking quantification of important reference measures (e.g. granule cell number) and evaluation of maturational markers whose persistence might be functionally more relevant than proliferation rates. Likewise, the confusion about the functional role of variations in adult hippocampal neurogenesis has many causes. Prominent is an inferential statistical approach, usually with low statistical power. Interpretation is complicated by multiple theories about hippocampal function, often unrealistically extrapolating from humans to rodents. We believe that the field of mammalian adult neurogenesis needs more critical thinking, more sophisticated hypotheses, better statistical, technical and behavioral approaches, and a broader conceptual perspective incorporating comparative aspects rather than neglecting them.

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Strain Background Influences Neurotoxicity and Behavioral Abnormalities in Mice Expressing the Tetracycline Transactivator

Cited by 89 publications

References 56 publications

Tau Overexpression Impacts a Neuroinflammation Gene Expression Network Perturbed in Alzheimer’s Disease

Tau Overexpression Impacts a Neuroinflammation Gene Expression Network Perturbed in Alzheimer’s Disease

The anti-inflammatory glycoprotein, CD200, restores neurogenesis and enhances amyloid phagocytosis in a mouse model of Alzheimer's disease

Adult Neurogenesis in Mammals: Variations and Confusions

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