MAST CELL HYPERACTIVATION INDUCES BEHAVIORAL DEFICITS AND CEREBRAL PERFUSION REDUCTION IN MICE

Abstract

There is growing evidence that mast cells are involved in Alzheimer's disease (AD). In humans they are associated with amyloid lesions, are degranulated by β-amyloid in mouse tissue culture and brain slices, and their increased presence is associated with later appearance of amyloid plaques in mice [1 and refs within]. Additionally, an AD clinical trial targeting mast cells with the inhibitor Masitinib (AB Science) stabilized cognitive scores [2]. To test directly if their overactivation can cause AD-like symptoms, we evaluated the KitD814V mouse model of mast cell hyperactivation [3], previously uncharacterized for CNS effects. KitD814V mice under the control of the mature-onset promoter Mctp5 (n=11) and their Mcpt5-only controls (n=7) were used. Due to likely variable age-related penetrance [3] and uncertain gender dimorphism, both groups included males and females 6–12 months old (equal per-group distribution). Mice were evaluated by MRI for brain morphology and cerebral perfusion, and behaviorally for anxiety/risk assessing (6 min elevated plus maze) and 24hr displacement activity (Noldus PhenoTyper). Statistics are presented as mean±SEM; p-values are from t-tests, with the significance threshold set at p≤0.05. Mcpt5-KitD814V mice, when compared to Mcpt5-only controls, exhibited a deficit in cerebral perfusion (112±13 vs. 155±12 ml 100g-1 min-1, p=0.026) though not one in brain volume (422±6 vs. 440±7 mm3, p=0.075). Behaviorally, deficits were also seen in elevated plus maze head dip total duration (risk-assessing behavior; 3.57±1.55 vs. 10.61±2.57 seconds, p=0.040) and 24hr displacement activity (294±40 vs. 494±54 meters, p=0.036). Mast cell hyperactive mice suffer behavioral deficits and exhibit perfusion reduction, a human biomarker of AD. This provides further evidence of the potential role of mast cells in dementia, and highlights the potential value of the KitD814V mouse as a model of it.