Compromised hemodynamic response in amyloid precursor protein transgenic mice

Abstract

APP23 transgenic mice overexpressing amyloid precursor protein (APP751) reproduce neuropathological changes associated with Alzheimer's disease such as high levels of amyloid plaques, cerebral amyloid angiopathy, and associated vascular pathologies. Functional magnetic resonance imaging (fMRI) was applied to characterize brain functionality in these mice through global pharmacological stimulation. The cerebral hemodynamic response to infusion of the GABA(A) antagonist bicuculline was significantly reduced in aged APP23 mice compared with age-matched wild-type littermates. This is in part attributable to a compromised cerebrovascular reactivity, as revealed by the reduced responsiveness to vasodilatory stimulation by acetazolamide. The study shows that fMRI is a sensitive tool to phenotype genetically engineered animals modeling neuropathologies.

Fig. 1.

Temporal evolution of CBV_rel during infusion of the GABA_A antagonist bicuculline (1.5 mg/kg). For ΔCBV_% maps, 10 images were averaged for each interval (210 sec). Infusion of bicuculline:t = 0–720 sec. Multislice experiments were conducted using two transverse brain sections 0.38 mm (a) and −0.94 mm (b) relative to the bregma of a 15-month-old control and an age-matched APP23 mouse. In control littermates, a prominent increase in cortical CBV_rel has been observed throughout the bicuculline infusion. In contrast, the cortical response to bicuculline stimulation was clearly reduced in amplitude and delayed in an APP23 mouse. The more caudal section also reveals a CBV_rel increase in the thalamus. Thalamic ΔCBV_% values were smaller than those in the cortex and displayed a delayed onset. Similar amplitudes of ΔCBV_% during infusion of bicuculline have been observed in control and APP23 mice. ROIs indicated by white outlines in the somatosensory cortex and thalamus of the mouse brain in transverse slices 0.38 mm anterior (c) and 0.94 mm posterior (d) relative to the bregma, respectively, were used for quantitative analysis of the CBV_rel changes and corresponding anatomical images taken from the brain atlas (Rosen, 2000). S1, Primary somatosensory cortex; S2, secondary somatosensory cortex; LV, lateral ventricle; 3V, third ventricle; PVN, paraventricular thalamic nucleus;VA, ventral anterior thalamic nucleus.

Fig. 2.

ΔCBV_% changes in the cortical ROIs defined in Figure 1c after administration of bicuculline at a dose of 1 mg/kg (a) and acetazolamide (DIAMOX) at a dose of 30 mg/kg (b) for 7.5- and 6-month-old APP23 mice and age-matched controls, respectively. Control and APP23 mice show similar ΔCBV_% changes. In aged mice (24 months of age), the cortical response to the infusion of bicuculline at a dose of 1.5 mg/kg (c) is significantly lower in transgenic animals compared with their littermates. The temporal profile after injection of acetazolamide (arrows) for 25-month-old APP23 mice and age-matched controls again revealed significantly lower ΔCBV_% changes in transgenic animals compared with their littermates (d). Ptc_CO2values obtained during online monitoring are shown at thebottom (e, f). Gray bars indicate the different infusion rates of the first 2 and subsequent 10 min. Data represent mean ± SEM.

Fig. 3.

Averaged ΔCBV_% during the total infusion period for cortical (a) and thalamic (b) ROIs revealed a significantly reduced response in 24-month-old APP23 mice compared with their littermates for bicuculline at a dose of 1.5 mg/kg and acetazolamide at a dose of 30 mg/kg (*p < 0.05 and **p < 0.01; ANOVA) at 24 and 25 months of age, respectively. Infusion of bicuculline at a dose of 1 mg/kg in 7.5-month-old mice revealed no significant difference between control and APP23 mice (ttest). Values are given as mean ± SEM. ^##Note the lower dose of 1 mg/kg at 7.5 months of age.