Research Models

PLB1-triple (hAPP/hTau/hPS1)

Synonyms: PLB1(Triple)

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Species: Mouse
Genes: APP, MAPT, PSEN1
Mutations: APP V717I (London), APP K670_M671delinsNL (Swedish), PSEN1 A246E, MAPT P301L, MAPT R406W
Modification: APP: Multi-transgene; MAPT: Multi-transgene; PSEN1: Multi-transgene
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: C57BL6
Availability: Available through Bettina Platt

Summary

The PLB1-triple model expresses low levels of mutant human APP, tau, and presenilin-1. The mice develop subtle age-related pathologies in the hippocampus and cortex, including accumulation of intraneuronal Aβ, a variety of oligomeric Aβ assemblies, gliosis, and hyperphosphorylated tau. Unlike models with high overexpression of disease genes, PLB1-triple mice do not develop neurofibrillary tangles and plaques are virtually absent. However, the mice develop specific age-related cognitive deficits in learning and memory tasks, along with abnormalities in hippocampal plasticity, EEG activity, and brain metabolism (Platt et al., 2011).

The PLB1-triple model, which takes its name from the investigator (Platt, Bettina), was created by first generating a model expressing low levels of human APP and tau and then crossing it with a previously existing mutant PSEN1 mouse, described as asymptomatic (Borchelt et al., 1997; Jyoti et al., 2010). The APP/tau construct was targeted to a permissive site on the X chromosome, the HPRT locus. This strategy allows for stable single-copy insertion, bypassing the potential confounds associated with random insertion such as transgenic mutagenesis and the misregulation of essential genes. In this model, endogenous APP, MAPT, and PSEN genes are intact. The APP/tau transgene is under the control of the mouse CaMKII-α promoter, and forebrain-specific expression was verified by immunohistochemistry, in situ hybridization, and PCR at 6 and 12 months of age. Because the transgene is inserted on the X chromosome, mutant male mice are always hemizygous for the transgene, whereas females can be either heterozygous or homozygous. Due to X chromosome inactivation, homozygous females have roughly equivalent transgene expression as hemizygous males.

Taken together, the phenotypes exhibited by PLB1-triple mice model early-stage degenerative processes rather than end-stage dementia. The overt neuropathology in this model is fairly mild and develops slowly. The mice display low levels of extracellular protein accumulation with sparse Aβ plaques by 6 months, and only slightly more by 21 months. However, aggregated Aβ was elevated by 12 months relative to wild-type littermates, and intraneuronal APP/Aβ also increased. A variety of oligomeric Aβ assemblies have been reported, including Aβ*56 (Plucińska et al., 2014). Age-related tau pathology was apparent starting around 6 months of age, including intraneuronal accumulations of phosphorylated tau.

Behaviorally, PLB1-triple mice develop impairments in tasks that measure learning and memory (Platt et al., 2011; Ryan et al., 2013). Social recognition memory was impaired by 5 months and further impaired by 12 months. Similarly, object recognition memory was impaired by 8 months. Spatial learning impairments were seen later; at 5 months spatial acquisition learning was intact as measured by the open-field water maze, but deficits developed by 12 months. Further training ameliorated the acquisition deficit. Sensory-motor abilities were intact, and in fact, PLB1-triple mice swam faster than controls at both five and 12 months.

PLB1-triple mice exhibit other phenotypes indicative of early pathological changes, including cortical hypometabolism; however, increased metabolic activity has been observed in the basal forebrain and ventral midbrain by FDG PET/CT. They also have exaggerated changes in sleep and EEG activity compared with wild-type, including increased wakefulness and severe fragmentation of REM and non-REM sleep by 9 months of age. Specific changes in EEG activity were measured as early as 5 months with robust changes from 13 months onward during wakefulness and non-REM sleep (Jyoti et al., 2015).  Electrophysiological studies indicate that basic synaptic transmission is intact at 6 months but affected at 12 months of age, and LTP following theta-burst stimulation decayed faster in PLB1-triple mice relative to littermate controls, despite normal post-tetanic potentiation. Similarly, paired-pulse facilitation, a measure of presynaptic short-term plasticity and transmitter release, was reduced in PLB1-triple mice at both 6 and 12 months of age (Platt et al., 2011; Koss et al., 2013).

Modification Details

To generate PLB1-triple animals, the researchers first created the PLB1-double mouse line expressing mutant human APP and tau, and then crossed it with a pre-existing presenilin line, hPS1 (A246E) transgenic mice (Borchelt et al., 1997; Jyoti et al., 2010). The PLB1-double line entailed  targeting a mutant human APP/tau cDNA construct to the HRPT site on the X chromosome. The transgene, driven by the mouse CaMKII-α promoter, consisted of human APP (isoform 770) with the Swedish and London mutations and human tau (isoform 2N/4R, 441 amino acids) with P301L and R406W mutations. To stabilize expression, an artificial intron was fused to the regulatory element and an IRES sequence was inserted between the two gene sequences. In addition, hAPP and hTau were flanked by loxP and FRT sites, respectively, allowing for excision of either sequence and the creation of, for example, the tau-only model (PLB2-Tau) (Calamai et al., 2013).

Availability

Available through Bettina Platt with MTA.

 

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Plaques
  • Tangles
  • Neuronal Loss

No Data

  • Synaptic Loss

Plaques

Sparse plaques out to 21 months of age. Only marginally increased compared with wild-types and overall very low compared to over-expression models. However, Aβ accumulated intracellularly and also formed oligomers.

Tangles

No overt tangle pathology; however, hyyperphosphorylated tau accumulated in the hippocampus and cortex from six months of age.

Neuronal Loss

Absent.

Gliosis

Increased inflammation (GFAP labelling) detected at 12 months in cortex and hippocampus (Platt, unpublished observation).

Synaptic Loss

Unknown.

Changes in LTP/LTD

Impairments in long-term and short-term hippocampal plasticity. LTP following theta-burst stimulation decayed faster and paired-pulse facilitation was reduced relative to wild-type mice at both six and 12 months of age. Synaptic transmission impacted at 12 months.

Cognitive Impairment

Social recognition memory was impaired by five months and further impaired by 12 months. Similarly, object recognition memory was impaired by eight months. Spatial learning impairments were seen later; at 12 months deficits in spatial acquisition learning were seen in the open field water maze that were not apparent at 5 months.

Last Updated: 04 Sep 2015

COMMENTS / QUESTIONS

  1. "Aβ levels were below the sensitivity limit of commercially available ELISAs (tested in tissue form 12-month-old mice; data not shown)." This tells everything about the mice.

    View all comments by Takaomi Saido

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References

Paper Citations

  1. Platt B, Drever B, Koss D, Stoppelkamp S, Jyoti A, Plano A, Utan A, Merrick G, Ryan D, Melis V, Wan H, Mingarelli M, Porcu E, Scrocchi L, Welch A, Riedel G. Abnormal cognition, sleep, EEG and brain metabolism in a novel knock-in Alzheimer mouse, PLB1. PLoS One. 2011;6(11):e27068. PubMed.
  2. Borchelt DR, Ratovitski T, van Lare J, Lee MK, Gonzales V, Jenkins NA, Copeland NG, Price DL, Sisodia SS. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron. 1997 Oct;19(4):939-45. PubMed.
  3. Jyoti A, Plano A, Riedel G, Platt B. EEG, activity, and sleep architecture in a transgenic AβPPswe/PSEN1A246E Alzheimer's disease mouse. J Alzheimers Dis. 2010;22(3):873-87. PubMed.
  4. Plucińska K, Crouch B, Koss D, Robinson L, Siebrecht M, Riedel G, Platt B. Knock-in of human BACE1 cleaves murine APP and reiterates Alzheimer-like phenotypes. J Neurosci. 2014 Aug 6;34(32):10710-28. PubMed.
  5. Ryan D, Koss D, Porcu E, Woodcock H, Robinson L, Platt B, Riedel G. Spatial learning impairments in PLB1Triple knock-in Alzheimer mice are task-specific and age-dependent. Cell Mol Life Sci. 2013 Jul;70(14):2603-19. PubMed.
  6. Jyoti A, Plano A, Riedel G, Platt B. Progressive age-related changes in sleep and EEG profiles in the PLB1Triple mouse model of Alzheimer's disease. Neurobiol Aging. 2015 Oct;36(10):2768-84. Epub 2015 Jul 8 PubMed.
  7. Koss DJ, Drever BD, Stoppelkamp S, Riedel G, Platt B. Age-dependent changes in hippocampal synaptic transmission and plasticity in the PLB1(Triple) Alzheimer mouse. Cell Mol Life Sci. 2013 Feb 14; PubMed.
  8. Calamai E, Dall'angelo S, Koss D, Domarkas J, McCarthy TJ, Mingarelli M, Riedel G, Schweiger LF, Welch A, Platt B, Zanda M. 18F-barbiturates are PET tracers with diagnostic potential in Alzheimer's disease. Chem Commun (Camb). 2013 Jan 28;49(8):792-4. PubMed.

Other Citations

  1. Bettina Platt

Further Reading

Papers

  1. Platt B, Welch A, Riedel G. FDG-PET imaging, EEG and sleep phenotypes as translational biomarkers for research in Alzheimer's disease. Biochem Soc Trans. 2011 Aug;39(4):874-80. PubMed.