Genes: APP, PSEN1
Mutations: APP KM670/671NL (Swedish), PSEN1 M146V
Modification: APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: B6;CB-Tg(Thy1-PSEN1*M146V/Thy1-APP*swe)10Arte
Genetic Background: Co-injection of transgenes into B6CBF1 oocytes, back-crossed to C57BL/6
This double transgenic mouse model of Alzheimer’s disease expresses mutant forms of human APP and PSEN1. Early amyloid pathology progresses rapidly and predictably with low inter-animal variability and no gender effects. In addition to reliable amyloid pathology, this model has other practical advantages, including efficient breeding capabilities and a low rate of premature death for both hemizygous and homozygous mice.
Plaque pathology in ARTE10 mice is robust, appearing first in the anterior neocortex and the subiculum, as early as three months of age in homozygous animals, and five months in hemizygotes. Plaques then spread to other regions, including the posterior neocortex, hippocampus, amygdala, and thalamus. The cerebellum is spared even in aged mice. The onset, rate, and maximum level of plaque deposition are dependent on transgene dosage, with plaques accumulating earlier and faster in homozygotes, and reaching higher levels overall. Notably, plaque pathology is relatively consistent between animals, with complete penetrance of the phenotype by five months of age in homozygotes and by 10 months in hemizygotes (Willuweit et al., 2009).
Plaques primarily take the form of congophilic dense-core structures, with lower levels of diffuse plaques, which are described as small satellites in proximity to mature plaques. Amyloid also accumulates in intracortical and leptomeningeal blood vessels. Plaques are composed of both Aβ40 and Aβ42, and accompanied by activated microglia and reactive astrocytes. Dense-core plaques are surrounded by dystrophic neurites, a minority of which contain hyperphosphorylated tau by eight months of age. Significant tau pathology (e.g. tangles, neuropil threads) was not observed in animals aged up to 20 months (Willuweit et al., 2009).
Outright neuronal loss has not been documented in ARTE10 animals, but morphometric analysis of hippocampal neurons has shown substantial shrinkage of the dendritic arbor. At around one year of age, the average neuron in hemizygous animals exhibited about 20 percent reductions in dendritic length, surface area, and number of dendritic branches compared to wild-type neurons. No differences were detected at two to four months of age, ruling out developmental differences. Reduced spine density was also observed in some regions of the hippocampus, along with a decrease in synaptic proteins (e.g., synaptophysin) as early as three to four months of age in both homozygous and hemizygous animals (Willuweit et al., 2009; Šišková et al., 2014).
The degeneration of the neuronal arbor in ARTE10 mice is thought to underlie the electrophysiological abnormalities observed in these animals, namely neuronal hyperexcitability in the form of higher firing frequencies and a propensity for bursting. Computational analysis predicts that the hyperexcitability of these neurons may be a direct result of the dendritic degeneration, which significantly reduces the overall surface area of the neuron(Šišková et al., 2014).
Behaviorally, these mice exhibit some age-associated cognitive deficits, mainly in episodic memory. Depending on the paradigm used, deficits were observed in an object-recognition task and in the Morris water maze at 12 months of age, but not at four and eight months (Willuweit et al., 2009).
In this model, transgene expression is driven by the Thy-1 promoter, resulting in targeted neuronal expression. The transgene was detected in about 80 percent of neurons in the hippocampus and about 50 percent of neurons in the neocortex. Transgene expression was not detected in glial cells, vascular smooth muscle cells, or endothelial cells of the brain (Willuweit et al., 2009).
These double transgenic mice express mutant APP carrying the K670N/M671L mutation and mutant PSEN1 carrying the M146V mutation. The transgenes are co-integrated and under the control of the Thy-1 promoter. The two transgenes are co-inherited, thus facilitating breeding to other mouse models.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Neuronal Loss
- Changes in LTP/LTD
Robust and reliable plaque pathology as early as 3 months in homozygotes, 5 months in hemizygotes. Plaques start in the anterior neocortex and subiculum, spreading to other brain regions (e.g. hippocampus, thalamus, amygdala). Congophilic dense-core plaques are abundant, with lower levels of diffuse plaques and some cerebral amyloid angiopathy.
No tangles or neuropil threads, but some hyperphosphorylated tau by eight months in dystrophic neurites.
Outright neuronal loss has not been documented, but substantial degeneration of dendritic arbors occurs by 10-14 months of age in hippocampal neurons.
Glial activation, including reactive astrocytes and activated microglia, is present in areas around plaques by 5 months of age in homozygous animals, later in hemizygotes.
Decreased expression of synaptophysin mRNA in the brain by 3-4 months of age in both hemizygous and homozygous animals.
Changes in LTP/LTD
Unknown; however, hippocampal neurons exhibit substantial changes in electrophysiological properties by 10-14 months of age, including hyperexcitability in the form of increased firing of action potentials and a more efficient transition from solitary firing to bursting.
Select, paradigm-dependent, deficits in learning and memory, especially episodic memory, by 12 months in homozygous and hemizygous mice.
- Willuweit A, Velden J, Godemann R, Manook A, Jetzek F, Tintrup H, Kauselmann G, Zevnik B, Henriksen G, Drzezga A, Pohlner J, Schoor M, Kemp JA, von der Kammer H. Early-onset and robust amyloid pathology in a new homozygous mouse model of Alzheimer's disease. PLoS One. 2009;4(11):e7931. PubMed.
- Šišková Z, Justus D, Kaneko H, Friedrichs D, Henneberg N, Beutel T, Pitsch J, Schoch S, Becker A, von der Kammer H, Remy S. Dendritic structural degeneration is functionally linked to cellular hyperexcitability in a mouse model of Alzheimer's disease. Neuron. 2014 Dec 3;84(5):1023-33. Epub 2014 Nov 13 PubMed.