Title:Reduced Serotonin Transporter Levels and Inflammation in the Midbrain Raphe of 12 Month Old APP<sub>swe</sub>/PSEN<sub>1dE9</sub> Mice
VOLUME: 15 ISSUE: 5
Author(s):Athanasios Metaxas*, Ramanan Vaitheeswaran, Katrine T. Jensen, Camilla Thygesen, Laura Ilkjaer, Sultan Darvesh and Bente Finsen
Affiliation:Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Department of Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia, Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense
Keywords:Alzheimer's disease, brainstem, dorsal raphe, median raphe, SERT, neuroinflammation, APPswe/PS1dE9.
Abstract:Background: Although mood and sleep disturbances are nearly universal among patients
with Alzheimer's disease (AD), brain structures involved in non-cognitive processing remain under
characterized in terms of AD pathology.
Objectives: This study was designed to evaluate hallmarks of AD pathology in the brainstem of the
APPswe/PS1dE9 mouse model of familial AD.
Methods: Fresh-frozen sections from female, 12 month old, transgenic and control B6C3 mice
(n=6/genotype) were examined for amyloid burden and neurofibrillary alterations, by using 6E10 immunohistochemistry
and the Gallyas silver stain, respectively. Serotonin transporter (SERT) densities in
the dorsal and the median raphe were quantified by [3H]DASB autoradiography. SERT mRNA expression
was measured by RT-PCR and visualized by in situ hybridization. Neuroinflammation was evaluated
by immunohistochemical staining for microglia and astrocytes, and by measuring mRNA levels of
the proinflammatory cytokines TNF-α, IL-1β and IL-6.
Results: No amyloid- and tau-associated lesions were observed in the midbrain raphe of 12 month old
APPswe/PS1dE9 mice. SERT binding levels were reduced in transgenic animals compared to age-matched
controls, and SERT mRNA levels were decreased by at least 50% from control values. Intense microglial,
but not astrocytic immunoreactivity was observed in APPswe/PS1dE9 vs. wild-type mice. Levels of
TNF-α mRNA were two-fold higher than control and correlated positively with SERT mRNA expression
levels in transgenic animals.
Conclusions: There was no amyloid accumulation and tau-associated pathology in the midbrain raphe
of 12 month old APPswe/PS1dE9 mice. However, there was a local neuroinflammatory response with loss
of serotonergic markers, which may partially account for some of the behavioral symptoms of AD.
