Genes: APP, PDGFRB
Mutations: APP KM670/671NL (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
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 APPsw/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.
These are progeny of APPsw transgenic mice, commonly known as Tg2576 (Hsiao et al., 1996), crossed with pericyte-deficient mice (Tallquist et al., 2003). APPsw 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.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Synaptic Loss
- Changes in LTP/LTD
Although mature neurofibrillary tangles were not observed by 9 months (the oldest age assessed), the mice develop significant tau pathology, including tau hyperphosphorylation in cortical and hippocampal neurons. Pre-tangle pathology is observed, including neuronal caspase-cleaved tau, and conformational changes as indicated by the conformation-specific antibody MC1.
Progressive neuronal degeneration including reduced neurite density and reduced neuronal number in the cortex and hippocampus of APPsw/0; Pdgfrβ+/- mice at at nine months compared to age-matched APPsw/0; Pdgfrβ+/+ littermates.
By 9 months of age APPsw/0;Pdgfrβ+/- mice have an elevated plaque load in the cortex and hippocampus compared with age matched APPsw/0;Pdgfrβ+/+. littermates. They also have extensive cerebral amyloid angiopathy.
Changes in LTP/LTD
At nine months, APPsw/0;Pdgfrβ+/- mice perform poorly on several hippocampal-dependent behavioral tests including burrowing, nest construction, and novel object recognition, compared with age-matched APPsw/0;Pdgfrβ+/+ littermates.
Research Models Citations
- 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.
- 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.
- 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.
- Winkler EA, Sagare AP, Zlokovic BV. The pericyte: a forgotten cell type with important implications for Alzheimer's disease?. Brain Pathol. 2014 Jul;24(4):371-86. PubMed.