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3xTg-AD

3xTg-AD

This disease model possess three mutations alleles, APPSwe, Psen1, and tauP301L. The APPSwe and Psen1 affect the beta-secretase and gama-secretase respectively, which would therefore induce the amyloidosis pathologies, such as both the intra- and extracellular Aβ deposition, together. 

The tauP301L, on the other hand, can induce the aggregation of 4R tau protein and thereby induce the tauopath, mainly in hippocampus and cortex, of the model. 

Together, the three mutations recapitulate both the tauopathy and amyloid pathologies in AD and can thereby be used as a more comprehensive disease model to study the inter-relationship between those two pathologies and their joint effect to the disease progression and pathologies, ranging from LTP deficits to synaptic transmission impairment, from cognitive deficits to gliosis.

Add Animal Model Information


Genetics

  • 3xTg model possess three mutant alleles, homozygous knock-in Presenilin1(Psen1) with PS1M146V mutation, homozygous APPSwedish (APPSwe) co-injection, and MAPT with P301L mutation, which implicate with the gama-secretase, the beta-secretase, and the neurofibrillary tangle tau protein, respectively. (The Jackson Laboratory)
  • The transgenes are integrated at a locuse in chromosome 2 and lead to the deletion of 3 base pair, but no gene is known to be affected.(ALZFORUM)
  • The translation, and thus the overexpression of these transgenes are localized to the CNS, especially in regions most vulnerable to AD’s pathologies such as cerebral cortex and hippocampus.(The Jackson Laboratory)
  • This mice models are fertile and viable with no initial gross behavioral or physical abnormalities.(The Jackson Laboratory)
  • Suggested Control (Genetic Background): B6129SF2/J(The Jackson Laboratory)

Amyloid

  • This strain possess:
    1. The APPSwe mutation, which can increase the APP cleavage by β-secretase and thus increase the production of Aβ40 and Aβ42.
    2. The Psen1 mutation, which can affect the presenilin 1, and therefore the cleavage activity of γ-secretase, to increase the production ratio of Aβ42 (a more toxic form) to Aβ40, and thereby aggravating the amyloid pathologies.
  • Therefore, 3xTg exhibit significant amyloid pathologies and recapitulate this property of AD.
  • Cortical plaques become detectable at 12 months.(The Jackson Laboratory)
  • Intracellular immunoreactivity of progressive Aβ deposition can be detected in some brain regions since 3 to 4 months.(The Jackson Laboratory)
  • While the progressive extracellular Aβ deposits onset by 6 months in the frontal cortex (mainly in layers 4 and 5) and aggravate by 12 months.(ALZFORUM)
  • Intraneuronal Aβ clearance with immunotherapy can rescues the early cognitive dysfunction in the hippocampal-dependent task.(ALZFORUM)
  • The accumulation of intraneuronal Aβ in amygdala and hippocampus are implicate with the cognitive deficit in long-term retention.(ALZFORUM)
  • In RGC layer, progressive Aβ plaques aggregation onset at about 5-10 weeksl as observed via confocal analysis of Aβ staining, which is absent in age-matched non-transgenic control.(Grimaldi, A., et al. (2018))
  • In outer layer of retina, progressive Aβ plaques aggregation onset between 30-40 weeks.(Grimaldi, A., et al. (2018))
  • In inner layer of retina, Aβ plaques appear during 30-40 weeks.(Grimaldi, A., et al. (2018))
  • In retina, the Aβ plaques are in direct contact with Iba1+ microglia, implicating the microgliosis due to amyloidosis.(Grimaldi, A., et al. (2018))

Tauopathy

  • This strain possess the MAPT P301L mutations, which will cause the aggregation and deposition of tau protein (4-Repeat 4R isoform).
  • Therefore, this model can exhibit and recapitulate the tauopathy property of AD and can thereby serve as a disease model to investigate the contribution and effect of tauopathy to AD disease progression.
  • The onset of tauopathy is relatively late and is not observed at 6 months.(ALZFORUM)
  • In CA1 neurons of hippocampus, especially pyramidal neurons, and later in cortex, there are extensive tau immunoreactivity.(ALZFORUM)
  • In hippocampus, aggregation of hyperphosphorylated and conformationally altered tau protein are detectable between 12 to 15 months.(The Jackson Laboratory)(ALZFORUM)
  • In retinal, the endogenous Tau level is altered in 3 and 6 months(Grimaldi, A., et al. (2018))
  • In RGC layer, tangles of pTau are detectable via immunostaining between 5-10 weeks.(Grimaldi, A., et al. (2018))
  • In outer layer of retina, tangles with significantly increased volume appear.(Grimaldi, A., et al. (2018))
  • In contrast, in non transgenic retina, no signal of tau was detected.(Grimaldi, A., et al. (2018))
  • In inner layer of retina, Tau tangles appear during 30-40 weeks.(Grimaldi, A., et al. (2018))

Synaptic Dysfunction

  • Synaptic deficits such as LTP deficits onset earlier than the tangles and plaques.(ALZFORUM)
  • LTP and synaptic transmission impairment can be demonstrated at 6 months.(The Jackson Laboratory)

Cognitive Deficits

  • Cognitive deficit is observable by 4 months, prior to the tangles and plaques.(ALZFORUM)
  • Deficits in retrieval or retention, instead of learning deficit, are the first manifestation of the cognitive deficits and they are implicated with the intraneuronal Aβ accumulation in amygdala and hippocampus.(ALZFORUM)
  • Cognitive deficits can be observed in both contextual and spatial based paradigms.(ALZFORUM)
  • Memory and learning dysfunctions can be displayed in Barnes maze at 6.5 months, but on the other hand, the mutant have a better performance than B6129SF2 wild-type in fear conditioning and Y maze tasks.(ALZFORUM)
  • The early cognitive dysfunctions in hippocampal-dependent task can be rescued by the clearance of intraneuronal Aβ with immunotherapy.(ALZFORUM)
  • LTP declines compared with wild type controls by 6 months.(ALZFORUM)
  • Basal synaptic transmission is also impaired(ALZFORUM)

Gliosis

  • Increased density of GFAP immunoreactive astrocytes and IBA-1 immunoreactive microglia compared with wild-type mice at 7 months (Caruso et al., 2013). Development of gliosis may occur earlier.(ALZFORUM)
  • Astrogliosis:
    Density of GFAP immunoactive astrocytes is elevated in mutant compared with wild type at 7 months.(ALZFORUM)
  • Microgliosis:
    Density of IBA-1 immunoreactive microglia is elevated in mutant compared with wild type at 7 months.(ALZFORUM)
  • However, The onset of the gliosis development might be earlier.(ALZFORUM)
  • In retina, significant astrogliosis, detected via confocal analysis of GFAP staining, was observed already at 5-10 weeks, with reactive astrocytes in granular cell layer. This higher GFAP immunoreactivity is observed at pre-symptomatic(5-20 weeks) and early-symptomatic stages(30-40 weeks) but becoming similar to non-transgenic retina at late stage(50-80 weeks).(Grimaldi, A., et al. (2018))
  • In retina, microglia first exhibit the phenotype as anti-inflammatory and ramified but, along the AD progression, switches to the phenotype as less ramified, pro-inflammatory and neurotoxic.(Grimaldi, A., et al. (2018))
  • In retina. the microglia density was akin between 3xTg and control at 5-40 weeks, but highly surge in 3xTg in late-symptomatic stage (50-80 weeks).(Grimaldi, A., et al. (2018))
  • In retina, the microglial arborization is higher then the non-transgenic at 5-10 weeks, as observed in the skeletonized image from confocal z-stack acquisitions. The retinal microglia in this stage also have higher gene expression of the typical anti-inflammatory and neuroprotective genes such as CD206 and Ym1 than the age-matched control.(Grimaldi, A., et al. (2018))
  • Nonetheless, the differences in retinal microglial ramification between 3xTg and wild-type vanish at early-symptomatic stage(30-40 weeks), as revealed via longitudinal analysis. Moreover, along the progression of AD, the gene expression of those anti-inflammatory and neuroprotective genes are also significantly subside while the expression of the neurotoxic and pro-inflammatory genes such as il1β and iNOS drastically surge from the initial low level.(Grimaldi, A., et al. (2018))
  • Furthermore, compared to control, the retinal microglial ramification is even less in 3xTg, with a lower morphological index, during AD progression in late-symptomatic stage(50-80 weeks)(Grimaldi, A., et al. (2018))
  • In retina, the microglia are in direct contact with the Aβ plaques in the pre-symptomatic stage(5-20 weeks) as revealed via the co-immunostaining of Iba1 and Aβ, implicating the potential contribution of amyloidosis to microgliosis.(Grimaldi, A., et al. (2018))

Neurodegeneration

  • The onset of retina neurodegeneration, manifested as the decrement in RGC number, start from 6 months.(Grimaldi, A., et al. (2018))
  • In RGC layer, the staining of cleaved caspase-3 puntate was observable via confocal immunofluorescence analysis already at 5 weeks and the percentage of caspase-3+ cells is signficantly and progressive higher in 3xTg than in the age-matched non transgenic mice.(Grimaldi, A., et al. (2018))

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