Mutations: APP KM670/671NL (Swedish), APP E693G (Arctic)
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: Origin: B6D2 F1
These mice overexpress human APP695 with the Swedish (K670N/M671L) and Arctic (E693G) mutations.
By six months of age, these mice develop amyloid pathology affecting both the brain parenchyma and vasculature. In the parenchyma, amyloid pathology starts as intracellular punctate Aβ deposits in the cortex and hippocampus. Plaques are abundant in these areas by 9 to 15 months (Knobloch et al., 2007; Merlini et al., 2011). In 11-month-old animals, amyloid plaques occupy 3.2 to 7.4 percent of the cortical surface, increasing to 11.9 to 18 percent at 21 months (Grandjean et al., 2014).
Severe cerebral amyloid angiopathy is also present by 9 to 15 months of age, with dense Aβ aggregates accumulating in the walls of blood vessels (Knobloch et al., 2007). Vascular amyloid leads to narrowing of the vessels, leakages, and loss of vascular smooth-muscle cells, resulting in blood-brain barrier disruption (Merlini et al., 2011).
Cognitive impairment is seen at 6 months of age as measured by the Morris water maze and Y-maze (Knobloch et al., 2007).
Prior to plaque accumulation, these mice develop early deficits in synaptic plasticity. Specifically, LTP was impaired in slices from 3.5- and 7.5-month-old mice. LTP and basal synaptic transmission are normal at 1 month (Knobloch et al., 2007). Functional connectivity deficits have also been observed from an early age. The development of functional connectivity in the somatosensory and motor cortex, as derived from the temporal correlation of resting-state fMRI signals, occurs during the first month of life in wild-type mice and is impaired in age-matched ArcAβ mice. Structural development, as measured by diffusion-tensor imaging, is also affected during early postnatal life (Grandjean et al., 2014).
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
Between 9 and 15 months of age β-amyloid plaques became prominent. Plaques had a characteristic dense core morphology which differed from the cotton wool-like structure of plaques seen with the Swedish mutation alone (Knobloch et al., 2007).
Changes in LTP/LTD
LTP is severely impaired in slices from 3.5 and 7.5 month old mice. LTP and basal synaptic transmission were normal in slices from one month old mice (Knobloch et al., 2007).
- Knobloch M, Konietzko U, Krebs DC, Nitsch RM. Intracellular Abeta and cognitive deficits precede beta-amyloid deposition in transgenic arcAbeta mice. Neurobiol Aging. 2007 Sep;28(9):1297-306. PubMed.
- Merlini M, Meyer EP, Ulmann-Schuler A, Nitsch RM. Vascular β-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAβ mice. Acta Neuropathol. 2011 Sep;122(3):293-311. PubMed.
- Grandjean J, Schroeter A, He P, Tanadini M, Keist R, Krstic D, Konietzko U, Klohs J, Nitsch RM, Rudin M. Early alterations in functional connectivity and white matter structure in a transgenic mouse model of cerebral amyloidosis. J Neurosci. 2014 Oct 8;34(41):13780-9. PubMed.
- Knobloch M, Farinelli M, Konietzko U, Nitsch RM, Mansuy IM. Abeta oligomer-mediated long-term potentiation impairment involves protein phosphatase 1-dependent mechanisms. J Neurosci. 2007 Jul 18;27(29):7648-53. PubMed.
- Vodopivec I, Galichet A, Knobloch M, Bierhaus A, Heizmann CW, Nitsch RM. RAGE does not affect amyloid pathology in transgenic ArcAbeta mice. Neurodegener Dis. 2009;6(5-6):270-80. PubMed.