Impulsivity, decreased social exploration, and executive dysfunction in a mouse model of frontotemporal dementia

Jeugd, Anneke Van der; Vermaercke, Ben; Halliday, Glenda M.; Staufenbiel, Matthias; Götz, Jürgen

doi:10.1016/j.nlm.2016.01.007

Cited by 25 publications

(26 citation statements)

References 67 publications

(31 reference statements)

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“…A very recent publication reported early increases in risk-taking behavior in young TAU58/2 when tested in the light/dark paradigm, but no changes to exploration and activity in the OF arena, including in aged mice [23]. Our study found similar behavior in young TAU58/2 mice using the EPM paradigm, as well as hyperactivity in the OF in aged mice, consistent with findings in other tau transgenic lines [6,25].…”

Section: Discussionsupporting

confidence: 91%

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Disinhibition-like behavior in a P301S mutant tau transgenic mouse model of frontotemporal dementia

Przybyla

Stevens

Hoven

et al. 2016

Neuroscience Letters

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Frontotemporal dementia (FTD) presents clinically with behavioral changes including disinhibition. Mutations in the tau-encoding MAPT gene identified in familial cases of FTD have been used to generate transgenic mouse models of the human condition. Here, we report behavioral changes in a recently developed P301S mutant tau transgenic mouse, including disinhibition-like behavior in the elevated plus maze and hyperactivity in the open field arena. Furthermore, histological analysis revealed the amygdala as a primary and early site of pathological tau deposition in these mice. Taken together, neuropathological and behavioral changes in P301S tau transgenic mice resemble features of human FTD. Disciplines Medicine and Health Sciences | Social and Behavioral Sciences Publication DetailsPrzybyla, M., Stevens, C. H., van der Hoven, J., Harasta, A., Bi, M., Ittner, A., van Hummel, A., Hodges, J. R., Piguet, O., Karl, T., Kassiou, M., Housley, G. Approximately one third of FTD cases are familial with the most frequent mutations found in the tau-encoding MAPT 13 gene with tau pathology, and in GRN and C9ORF72 associated with TDP-43 deposition [10]. Interestingly, behavioral 14 disinhibition is more frequent amongst MAPT, than GRN and C9ORF72 mutation carriers with familial FTD [21]. 15 16 Tau is an unstructured multi-domain protein that binds to microtubules to regulate their dynamics and intracellular 17 transport processes [2]. Tau is predominantly found in the axon of neurons, although small amounts localize to the post -18 synapse to regulate excitatory signaling [15]. Tau harbors over 80 potential phosphorylation sites, and in disease, it 19 becomes aberrantly phosphorylated at many sites, which coined the term 'hyperphosphorylated tau' [11]. 20Hyperphosphorylation of tau compromises its binding to microtubules, resulting in accumulation of tau in the soma and 21 dendrites of neurons [13]. Hyperphosphorylated tau is prone to oligomerize and form insoluble fibrillar aggregates that 22 present as neurofibrillary tangles (NFTs), a common feature of FTD with tau pathology [5]. 23 24 The identification of MAPT mutations in familial FTD has been instrumental in the generation of a significant number 25 of transgenic mouse lines that develop functional deficits and NFT pathology (reviewed by [12]). We have recently 26 reported TAU58/2 mice with neuronal expression of P301S mutant tau [24]. TAU58/2 mice present with motor deficits , 27 and tau and neurofillament pathology reminiscent of human FTD with tau pathology. In the present study, we show that 28 TAU58/2 mice develop early-onset disinhibition-like behavior and increased motor activity together with early NFT 29 pathology in the amygdala, reminiscent of bvFTD. Open Field 5Activity, anxiety and exploration pattern were tested in 3, 6 and 10 month-old male TAU58/2 mice (n=6-17) and non-6 transgenic littermates (n=6-13) in an open field arena. Mice were individually placed at the periphery of a box (40cm x 7 40cm) in an enclosed cupboard and their movement ...

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Section: Discussionsupporting

confidence: 91%

“…Previous studies have not assessed tau pathology in the amygdala of TAU58/2 mice [23,24]. While we found earlier that tau pathology presents in hippocampus, cortex and brain stem of TAU58/2 mice [24], the present study would suggest that the amygdala is a primary site of NFT pathology in this tau transgenic line .…”

Section: Discussioncontrasting

confidence: 62%

Disinhibition-like behavior in a P301S mutant tau transgenic mouse model of frontotemporal dementia

Przybyla

Stevens

Hoven

et al. 2016

Neuroscience Letters

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“…Early aggregation events were probed for using the T22 antibody, which is specific to an oligomeric confirmation [154] and mature NFT formation was investigated using traditional silver staining techniques Gallyas and Bielschowsky. Aged Tau58 mice carrying the FTD P301S mutation were used as positive controls for silver staining due to their well characterised NFT formation [92,237]. Western blotting of EV isolation for this study is consistent with previous work, confirming that fraction 3 (F3) is enriched in both exosome markers and tau (Fig.…”

Section: Experimental Designsupporting

confidence: 88%

“…Early aggregation events were probed for using the T22 antibody, which is specific to the oligomeric confirmation [154] and mature NFT formation was investigated using the traditional silver staining techniques Gallyas and Bielschowsky. Aged Tau58 mice carrying the FTD P301S mutation have well characterised NFT formation and were used as positive controls for the silver staining methodology [92,237]. To further address changes in tau solubility the other hemisphere underwent sequential fractionation in RAB and RIPA buffers to yield a soluble and insoluble protein fraction probed by western blotting with phosphospecific tau antibodies.…”

Section: Experimental Designmentioning

confidence: 99%

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

Baker¹

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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...

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“…The findings are more easily translatable to social withdrawal and communicative deficits. For example, it has been found that subjects spend increasingly less time interacting with others as dementia progresses (Van der Jeugd et al, 2016). Surprisingly, no significant effects of housing conditions were found, possibly meaning that social exploration has an essential drive or motivation in social species, whether housed separate or not.…”

Section: Discussionmentioning

confidence: 99%

Social isolation impacts late-life socio-cognitive decline in APP/PS1 mice

Rens

D’Hooge

Jeugd

2019

Preprint

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In this study the effects of social isolation (SI) were investigated in APP/PS1 mice. It was found that SI during adolescence has an impact on anxiogenic behaviour, such that isolated animals tend to explore a threatening environment less than non-isolated animals as assessed with the EPM test, and that this holds for both AD and non-AD mice. While no evidence was found for any differences in short-term memory as assessed by the Y-maze, long-term memory seemed to be affected in a context-dependent manner. Object memory as assessed with the NOR test was affected in APP/PS1 mice compared to WT mice, but this deficit was not induced or influenced by SI. When it comes to social recognition memory however, we found that SI exacerbated the social memory deficit in AD mice, and even induced a deficit in WTs. Associative fear memory as assessed with the PA test suggested that WTs perform better when group housed, and APP/PS1 mice better when socially isolated. The link between isolation and AD, or cognition in general, may be more complex than initially thought. The effect of isolation may not be the same for AD versus non-AD subjects.

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Impulsivity, decreased social exploration, and executive dysfunction in a mouse model of frontotemporal dementia

Cited by 25 publications

References 67 publications

Disinhibition-like behavior in a P301S mutant tau transgenic mouse model of frontotemporal dementia

Disinhibition-like behavior in a P301S mutant tau transgenic mouse model of frontotemporal dementia

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

Social isolation impacts late-life socio-cognitive decline in APP/PS1 mice

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