Examination of Alzheimer’s-related positive, negative and reactive pathology in the brainstem of APPswe/PS1ΔE9 mice

Aim: While the positive, negative and reactive lesions of Alzheimer’s disease (AD) have been extensively characterised in brain areas associated with cognition, such as the cortex and the hippocampus, the status of subcortical structures in AD remains less well characterised. In the present study, we examined AD-related pathology in the midbrain brainstem of the APPswe/PS1ΔE9 mouse model of amyloidosis (APP/PS1).
Methods: For positive lesions, fresh-frozen brainstem sections from female, 12 months old, transgenic and control mice (n=6/genotype) were stained for amyloid beta and tau, using 6E10 immunohistochemistry and the Gallyas silver stain respectively. Negative lesions were examined by tryptophan hydroxylase (TPH) 2 immunohistochemistry, and by measuring binding and mRNA levels of the serotonin transporter (SERT). Reactive lesions were investigated by Iba1 immunostaining of microglial cells, and by measuring mRNA of the pro-inflammatory cytokines TNFα, IL-1β and IL-6.
Results: There were no plaques and tangles in the brainstem of 12 months old transgenic animals. SERT binding levels and TPH2 immunoreactivity were reduced in APP/PS1 mice compared with control, while SERT mRNA was unchanged between genotypes. Intense microglial staining was observed in the brainstem of transgenic mice. TNFα mRNA levels were two-fold higher over control. No difference in IL-1β and IL-6 mRNA was observed between APP/PS1 and wild-type animals.
Conclusions: These data indicate that negative and reactive lesions are present in the brainstem of 12 months old APP/PS1 mice, in the absence of local positive pathology. Our ongoing study implies that retrograde mechanisms must determine degeneration of brainstem serotonergic nuclei in the APP/PS1 model of amyloidosis.