Occurrence and co-localization of amyloid β-protein and apolipoprotein E in perivascular drainage channels of wild-type and APP-transgenic mice

Abstract

The deposition of the amyloid β-protein (Aβ) is a hallmark of Alzheimer's disease (AD). One reason for Aβ-accumulation and deposition in the brain may be an altered drainage along perivascular channels. Extracellular fluid is drained from the brain towards the cervical lymph nodes via perivascular channels. The perivascular space around cerebral arteries is the morphological correlative of these drainage channels. Here, we show that Aβ is immunohistochemically detectable within the perivascular space of 25 months old wild-type and amyloid precursor protein (APP)-transgenic mice harboring the Swedish double mutation driven by a neuron specific promoter. Only small amounts of Aβ can be detected immunohistochemically in the perivascular space of wild-type mice. Cerebrovascular and parenchymal Aβ-deposits were absent. In APP-transgenic mice, large amounts of Aβ were found in the perivascular drainage channels accompanied with cerebrovascular and parenchymal Aβ-deposition. The apolipoprotein E (apoE) immunostaining within the perivascular channels did not vary between wild-type and APP-transgenic mice. Almost 100% of the area that represents the perivascular space was stained with an antibody directed against apoE. Here, Aβ co-localized with apoE indicating an involvement of apoE in the perivascular clearance of Aβ. Fibrillar congophilic amyloid was not seen in wild-type mice. In APP-transgenic animals, congophilic fibrillar amyloid material was seen in the wall of cerebral blood vessels but not in the perivascular space. In conclusion, our results suggest that non-fibrillar forms of Aβ are drained along perivascular channels and that apoE is presumably involved in this clearance mechanism. Overloading such a clearance mechanism in APP-transgenic mice appears to result in insufficient Aβ-clearance, increased Aβ-levels in the brain and the perivascular drainage channels, and finally in Aβ-deposition. In so doing, our results strengthen the hypothesis that an alteration of perivascular drainage supports Aβ-deposition and the development of AD.