Early Alzheimer’s Biomarkers: Using the ARTE10 (APP-PS1) Mouse Model at 5 Months

The ARTE10 double transgenic mouse model, which expresses mutant forms of human APP (Swedish mutation) and human Presenilin 1 carrying the M146 mutation (PSEN1), serves as a translational preclinical model for studying Alzheimer's disease. Despite its potential, there is limited data available on various behavioral assays and relevant biomarkers across different time points in the ARTE10 model.

Our aim is to behaviorally and biochemically characterize the ARTE10 model across three time points, corresponding to early, middle, and late stages of amyloid progression. Currently, we present data from the first time point at 5 months of age.

At 5 months of age, ARTE10 mice exhibit increased anxiety-like behaviors, hyperactivity, deficits in sensory motor gating, and spatial working memory deficits. Additionally, these mice show biomarkers relevant to Alzheimer's disease, including increased amyloid load in the hippocampus and cortex, and trending differences in NfL and cytokines. Data at 10 months of age is coming soon!

Sensory motor gating- Prepulse inhibition (PPI)

Homozygous ARTE10 animals have an increased startle response and reduced PPI indicating deficits in sensory motor-gating compared to WT controls

Anxiety-like Behavior - Canopy Test

Anxiety-like behaviours are detected in homozygous ARTE10 animals at 5 months of age using the canopy test¹. ARTE10 animals also perform less risk-taking behaviours such as looking over the edge of the canopy maze.

Well-being-like Behavior - Nest Building

Nest complexity is indicative of an animal’s mood, motivation and well-being. ARTE10 animals do not build nests as complex as WT controls supporting a mood disturbance in these animals².

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Motor Function - Locomotor Activity (LMA)

Hypolocomotion in ARTE10 mice, is likely due to increased anxiety-like behavior in a novel environment. Animals prefer the outer edges and corners compared to the open center as shown in the path plots.

WT

ARTE10

Motor Function – Rotarod

ARTE10 animals show no motor function deficits using the rotarod at 5 months of age.

Motor Function - Running Wheel (20 hour recordings)

The running wheel provides information about natural activity levels during the animal's dark and light phases. ARTE10 mice are naturally hyperactive in the running wheel. This data supports the hypothesis that LMA hypoactivity may be anxiety related.

Learning and Memory - Morris Water Maze

Spatial learning is impaired in cued and place learning in ARTE10 mice. No differences in working memory were found during the probe test. Reversal learning was partially impaired in ARTE10 mice.

Biomarkers

Amyloid levels (Aβ40 and Aβ42) are increased in the cortex and hippocampus of ARTE10 animals as expected. There is a higher amyloid load in the cortex than the hippocampus at 5 months of age.

IFNγ, lL-1β, IL-6 and TNFα levels in plasma were quantified using a MSD kit. Cytokine levels are starting to increasing at this stage with trend level or significant effects in IFNγ, IL-1β and TNFα. Increased cytokines indicates increased inflammatory processes are present in the ARTE10 animals.

NfL levels in plasma, CSF, hippocampus and cortex were quantified using a MSD kit. NfL is a biomarker for neuronal damage. NfL levels are trending towards an increase in the CSF of ARTE10 animals at 5 months of age. No significant changes in plasma or brain were detected.