Species: Mouse
Genes: APP, PDGFRB
Mutations: APP K670_M671delinsNL (Swedish)
Modification: APP: Transgenic; PDGFRB: Knock-Out
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: APPsw mice on C57BL/6; Pdgfrβ+/- mice on 129S1/SvlmJ.
Availability: Available through Berislav Zlokovic

Summary

These mice model a “two-hit” hypothesis of Alzheimer’s disease, specifically elevated Aβ and vascular dysfunction. Aβ production is enhanced courtesy of a human APP transgene bearing the Swedish mutation, while vascular dysfunction is initiated by genetically reducing the number of pericytes, specialized vascular cells essential to the functioning of the blood-brain barrier.

Pericyte proliferation, migration, and recruitment to the vascular wall is regulated by the growth factor PDGFβ, and therefore, genetic disruption of the PDGFβ receptor gene triggers progressive pericyte deficiency. Consequently, Pdgfrβ mice develop blood-brain barrier dysfunction and reduced microcirculation in the brain, pathologies that are also observed in the AD brain. Although other mouse models have demonstrated that complete ablation of pericytes is lethal, the moderate pericyte reduction in this line does not compromise viability.

The APP transgenic mouse, APPsw, also known as Tg2576, expresses human APP with the Swedish double mutation, which causes a dramatic increase in total Aβ production. This transgenic line develops elevated Aβ, amyloid plaques, and memory deficits, but no significant tau pathology or neuronal loss (Hsiao et al., 1996). When crossed with pericyte-deficient mice, the resulting progeny have more extensive Aβ pathology by nine months of age as well as substantial cerebral amyloid angiopathy in cerebral vessels (Sagare et al., 2013). Human Aβ40 and Aβ42 accumulate in the brain and interstitial fluid, as does endogenous murine Aβ. Interestingly, murine Aβ does not accumulate in the Pdgfrβ^+/- alone, suggesting that at low, physiological levels, murine Aβ does not present a challenge to even a compromised vasculature, but the the additional high levels of Aβ produced from human APP with the Swedish mutation overwhelms the clearance capacity.

Notably, unlike the Tg2576 single transgenic, the APP^sw/0; Pdgfrβ^+/- double mutant develops tau pathology including hyperphosphoylated tau and early conformational changes in the protein that are thought to be precursors to mature tangles. Similarly, although neither line alone develops neuronal loss, the double mutants have extensive neuronal and neurite loss in the hippocampus and cortex by nine months of age. Behavioral deficits are also seen as evidenced by hippocampal-dependent tasks such as nest building, burrowing behavior, and the recognition of a novel object. The more extensive pathology seen in the double mutant supports the “two-hit” hypothesis by which elevated Aβ and dysfunction within the vasculature not only excerbate each other, but promote tau pathology, neurodegeneration, and cognitive impairment.

Modification Details

These are progeny of APP^sw transgenic mice, commonly known as Tg2576 (Hsiao et al., 1996), crossed with pericyte-deficient mice (Tallquist et al., 2003). APP^sw mice express human APP with the Swedish double mutation under the control of the hamster prion promoter. Pericyte-deficient mice were made by disrupting the PDGFRβ gene using a PGKneobpA expression cassette to replace a 1.8 kb genomic segment spanning the signal peptide to the second immunoglobulin domain of PDGFRβ. Heterozygous mice (Pdgfrβ^+/-) were used for the cross.

Phenotype Characterization

COMMENTS / QUESTIONS

No Available Comments

Make a comment or submit a question

To make a comment you must login or register.

References

Research Models Citations

1. Tg2576

Paper Citations

1. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science. 1996 Oct 4;274(5284):99-102. PubMed.
2. Sagare AP, Bell RD, Zhao Z, Ma Q, Winkler EA, Ramanathan A, Zlokovic BV. Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat Commun. 2013;4:2932. PubMed. Correction. RETRACTED
3. Tallquist MD, French WJ, Soriano P. Additive effects of PDGF receptor beta signaling pathways in vascular smooth muscle cell development. PLoS Biol. 2003 Nov;1(2):E52. Epub 2003 Nov 17 PubMed.

Other Citations

1. APPsw

Further Reading