Amyloid pathology induces dysfunction of systemic neurotransmission in aged APPswe/PS2 mice

Abstract

This study aimed to investigate how amyloid pathology affects the functional aspects of neurotransmitter systems in Alzheimer's disease. APPswe/PS2 mice (21 months of age) and wild-type (WT) mice underwent positron emission tomography (PET) and magnetic resonance spectroscopy (MRS). First, we obtained ¹⁸F-FDG and ¹⁸F-florbetaben PET scans to evaluate neuronal integrity and amyloid pathology. Second, ¹⁸F-FPEB and ¹⁸F-FMZ PET data were acquired to assess the excitatory-inhibitory neurotransmission. Third, to monitor the dopamine system, ¹⁸F-fallypride PET was performed. Amyloid PET imaging revealed that radioactivity was higher in the AD group than that in the WT group, which was validated by immunohistochemistry. In the cortical and limbic areas, the AD group showed a 25-27% decrease and 14-35% increase in the glutamatergic and GABAergic systems, respectively. The dopaminergic system in the AD group exhibited a 29% decrease in brain uptake compared with that in the WT group. A reduction in glutamate, N-acetylaspartate, and taurine levels was observed in the AD group using MRS. Our results suggest that dysfunction of the neurotransmitter system is associated with AD pathology. Among the systems, the GABAergic system was prominent, implying that the inhibitory neurotransmission system may be the most vulnerable to AD pathology.

Keywords: APPswe/PS2; Alzheimer’s disease; beta amyloid; neurotransmitter; positron emission tomography.

FIGURE 1

Definition of volumes of interest (VOIs) for all positron emission tomography (PET) tracers. Magnetic resonance (MR) images for the horizontal, coronal, and sagittal planes are presented. Spatially normalized PET images were applied to the VOIs for each radiotracer.

FIGURE 2

Summed positron emission tomography (PET) images (40–60 min) of ¹⁸F-FDG in the wild-type (WT) (A–C) and Alzheimer’s disease (AD) groups (D–F). In PET images, the columns from left to right show the axial, coronal, and sagittal views. Comparison of the standardized uptake values (SUVs) in terms of the target regions (G). Data are presented as the mean ± SD (n = 6).

FIGURE 3

Summed positron emission tomography (PET) images (10–30 min) of ¹⁸F-florbetaben in the wild-type (WT) (A–C) and Alzheimer’s disease (AD) groups (D–F). Comparison of the standardized uptake values (SUVs) for the brain regions (G) at 10–30 min. Values are presented as the mean ± SD (n = 6). Statistical significance was defined as a p value less than 0.05 for comparisons between groups (*p < 0.05, ***p < 0.001 and ****p < 0.0001).

FIGURE 4

Mean positron emission tomography (PET) images of ¹⁸F-FPEB [wild-type (WT) (A–C) and Alzheimer’s disease (AD) (D–F) at 40–60 min] and ¹⁸F-flumazenil [WT (G–I) and AD (J–L) at 30–50 min]. Quantification of the radioactivities for the ¹⁸F-FPEB (M) and ¹⁸F-flumazenil (N). Data are presented as the mean ± SD (n = 6). Statistical significance was defined as a p value less than 0.05 for comparisons between groups (**p < 0.01, ***p < 0.001, and ****p < 0.0001).

FIGURE 5

Mean positron emission tomography (PET) images of ¹⁸F-fallypride for wild-type (WT) (A–C) and Alzheimer’s disease (AD) groups (D–F). Comparison of the standardized uptake values (SUVs) for the striatum and cerebellum for ¹⁸F-fallypride at 30–50 min (G). Data are presented as the mean ± SD (n = 6). Statistical significance was defined as a p value less than 0.05 for comparisons between groups (****p < 0.0001).

FIGURE 6

Immunohistochemical staining of Aβ₄₂ peptide in the hippocampus for wild-type (WT) and Alzheimer’s disease (AD) mice (A–H). (A,B) 100× magnification of the hippocampus, (C–H) 400× magnification of the hippocampal regions such as CA1, CA2, and CA3 (Scale bar = 60 μm). The number of Aβ42 peptides in the CA1, CA2, and CA3 regions are expressed as mean ± SD (I, *p < 0.05, and **p < 0.005). This analysis was done for all mice (n = 5).

FIGURE 7

Definition of the volume of interest (i.e., dorsal hippocampus) in magnetic resonance spectroscopy (MRS) (A). Comparison of the neurochemical profiles between the wild-type (WT) and APPswe/PS2 mice (B). Data are presented as the mean ± SD (n = 5). A p-value < 0.05 was considered statistically significant (*p < 0.05).