Occurrence and co-localization of amyloid β-protein and apolipoprotein E in perivascular drainage channels of wild-type and APP-transgenic mice
Introduction
Alzheimer's disease (AD) is histopathologically characterized by the deposition of amyloid β-protein (Aβ) [4], [16]. Increased levels of Aβ are considered to be responsible for neurodegeneration in AD [9]. An increase of Aβ in the brain can either result from increased production or from decreased clearance of Aβ [15]. Transgenic mice overexpressing mutant amyloid precursor protein (APP) produce increased levels of Aβ and develop Aβ-plaques and cerebral amyloid angiopathy (CAA) [7], [10], [29]. APP23 mice overexpress human APP harboring the Swedish double mutation (670/671 KM ->NL) driven by the neuron specific Thy-1 promoter [29]. APP-overexpression is not seen in other tissues except the central nervous tissue of these mice [29]. Therefore, the APP23 mouse is an ideal model for studying the mechanisms of Aβ-deposition and Aβ-clearance. One clearance mechanism for Aβ from brain is binding to apolipoprotein E (apoE) [28] and the subsequent uptake by astrocytes [13]. However, apoE is also found in senile plaques in humans [20] and mice [22] and appears to be involved in the formation of newly formed plaques [31]. In addition to the cellular clearance of Aβ by astrocytes and microglial cells [11], [13] and the enzymatic degradation by neprilysin and/or insulin degrading enzyme [11], [19], drainage of extracellular Aβ along perivascular spaces has been discussed to play a significant role in Aβ-clearance [36]. Perivascular channels represent drainage channels for extracellular fluid from the brain towards the cervical lymph nodes [35], [40]. The perivascular space around cerebral arteries is the morphological correlative of these drainage channels [35], [40] (Fig. 1A). Although the development of CAA in transgenic mice overexpressing APP through a neuron-specific promoter strongly suggests clearance of Aβ along the perivascular channels [3], Aβ has not been shown to occur physiologically in these channels and it is not clear which forms of Aβ are drained.
Therefore, the aim of this study is to address the question whether non-fibrillar Aβ is present within the perivascular space of cerebral vessels and to examine the role of apoE in the perivascular drainage of Aβ.
Section snippets
Material and methods
To demonstrate the presence of Aβ within the perivascular space and to test whether apoE is involved in this drainage process, we studied brains from 25 months old, female wild-type (n = 20) and APP23 mice (n = 16) for the presence of Aβ and apoE within the perivascular channels of cerebral vessels. Animals were treated in agreement with the German law on the use of laboratory animals. Perfusion fixation of the animals was performed transcardially with Tris buffered saline (TBS) with heparin (pH
Results
Microscopic analysis of cerebral vessels revealed visible perivascular channels in all animals (Fig. 1B and C). The perivascular space was best seen at the level of the hippocampal formation around the posterior cerebral artery and its ramifications. Near and within perivascular channels no cellular reaction was detected (Fig. 1B and C). Only amorphous proteinaceous material was visible in the Hematoxylin and Eosin and Elastica van Gieson stained sections (Fig. 1C). Nearby blood vessels did not
Discussion
The presence of Aβ within the perivascular space of wild-type and APP23 mice strongly supports the hypothesis of Weller et al. [36] that drainage along these channels contributes to the clearance of Aβ from brain. Physiologically, low amounts of Aβ were detected immunohistochemically within these channels in wild-type mice. The absence of Congo red stained material indicates the non-fibrillar nature of the Aβ-positive material in these mice. As soon as the amount of neuronal derived Aβ is
Acknowledgements
The authors gratefully acknowledge the technical assistance of N. Kolosnjaji and H. U. Klatt.
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