ABSTRACT
BACKGROUND: ATP-binding cassette (ABC) transporters are essential regulators of organismic homeostasis, and are particularly important in protecting the body from potentially harmful exogenous substances. Recently, an increasing number of in vitro observations have indicated a functional role of ABC transporters in the differentiation and maintenance of stem cells. Therefore, we sought to determine brain-related phenotypic changes in animals lacking the expression of distinct ABC transporters (ABCB1, ABCG2 or ABCC1). METHODOLOGY AND PRINCIPAL FINDINGS: Analyzing adult neurogenesis in ABC transporter-deficient animals in vivo and neuronal stem/progenitor cells in vitro resulted in complex findings. In vivo, the differentiation of neuronal progenitors was hindered in ABC transporter-deficient mice (ABCB1(0/0)) as evidenced by lowered numbers of doublecortin(+) (-36%) and calretinin(+) (-37%) cells. In vitro, we confirmed that this finding is not connected to the functional loss of single neural stem/progenitor cells (NSPCs). Furthermore, assessment of activity, exploratory behavior, and anxiety levels revealed behavioral alterations in ABCB1(0/0) and ABCC1(0/0) mice, whereas ABCG2(0/0) mice were mostly unaffected. CONCLUSION AND SIGNIFICANCE: Our data show that single ABC transporter-deficiency does not necessarily impair neuronal progenitor homeostasis on the single NSPC level, as suggested by previous studies. However, loss of distinct ABC transporters impacts global brain homeostasis with far ranging consequences, leading to impaired neurogenic functions in vivo and even to distinct behavioral phenotypes. In addition to the known role of ABC transporters in proteopathies such as Parkinson's disease and Alzheimer's disease, our data highlight the importance of understanding the general function of ABC transporters for the brain's homeostasis and the regeneration potential.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP-Binding Cassette Transporters/metabolism , Multidrug Resistance-Associated Proteins/metabolism , Neurogenesis , Neurons/cytology , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/genetics , Animals , Anxiety/genetics , Anxiety/metabolism , Behavior, Animal , Brain/cytology , Brain/metabolism , Cell Proliferation , Cells, Cultured , Female , Gene Deletion , Male , Mice , Multidrug Resistance-Associated Proteins/genetics , Neurons/metabolism , Stem Cells/cytology , Stem Cells/metabolismABSTRACT
In Alzheimer disease (AD), the intracerebral accumulation of amyloid-ß (Aß) peptides is a critical yet poorly understood process. Aß clearance via the blood-brain barrier is reduced by approximately 30% in AD patients, but the underlying mechanisms remain elusive. ABC transporters have been implicated in the regulation of Aß levels in the brain. Using a mouse model of AD in which the animals were further genetically modified to lack specific ABC transporters, here we have shown that the transporter ABCC1 has an important role in cerebral Aß clearance and accumulation. Deficiency of ABCC1 substantially increased cerebral Aß levels without altering the expression of most enzymes that would favor the production of Aß from the Aß precursor protein. In contrast, activation of ABCC1 using thiethylperazine (a drug approved by the FDA to relieve nausea and vomiting) markedly reduced Aß load in a mouse model of AD expressing ABCC1 but not in such mice lacking ABCC1. Thus, by altering the temporal aggregation profile of Aß, pharmacological activation of ABC transporters could impede the neurodegenerative cascade that culminates in the dementia of AD.
Subject(s)
Amyloid beta-Peptides/metabolism , Brain/metabolism , Multidrug Resistance-Associated Proteins/metabolism , Alzheimer Disease/etiology , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Amyloid beta-Peptides/chemistry , Amyloid beta-Protein Precursor/chemistry , Amyloid beta-Protein Precursor/metabolism , Animals , Brain/blood supply , Brain/pathology , Disease Models, Animal , Humans , Mice , Mice, Knockout , Mice, Transgenic , Microvessels/metabolism , Multidrug Resistance-Associated Proteins/deficiency , Multidrug Resistance-Associated Proteins/genetics , Protein MultimerizationABSTRACT
One early and prominent pathologic feature of Alzheimer's disease (AD) is the appearance of activated microglia in the vicinity of developing ß-amyloid deposits. However, the precise role of microglia during the course of AD is still under discussion. Microglia have been reported to degrade and clear ß-amyloid, but they also can exert deleterious effects due to overwhelming inflammatory reactions. Here, we demonstrate the occurrence of developing plaque populations with distinct amounts of associated microglia using time-dependent analyses of plaque morphology and the spatial distribution of microglia in an APP/PS1 mouse model. In addition to a population of larger plaques (>700µm(2)) that are occupied by a moderate contingent of microglial cells across the course of aging, a second type of small ß-amyloid deposits develops (≤400µm(2)) in which the plaque core is enveloped by a relatively large number of microglia. Our analyses indicate that microglia are strongly activated early in the emergence of senile plaques, but that activation is diminished in the later stages of plaque evolution (>150 days). These findings support the view that microglia serve to restrict the growth of senile plaques, and do so in a way that minimizes local inflammatory damage to other components of the brain.
Subject(s)
Alzheimer Disease/pathology , Microglia/pathology , Plaque, Amyloid/pathology , Alzheimer Disease/genetics , Amyloid beta-Protein Precursor/genetics , Animals , Disease Models, Animal , Female , High-Throughput Screening Assays , Humans , Immunohistochemistry , Male , Mice , Mice, Transgenic , Presenilin-1/geneticsABSTRACT
In vivo imaging of amyloid-ß (Aß) load as a biomarker of Alzheimer's disease (AD) would be of considerable clinical relevance for the early diagnosis and monitoring of treatment effects. Here, we investigated automated quantification of in vivo T2 relaxation time as a surrogate measure of plaque load in the brains of ten AßPP/PS1 transgenic mice (age 20 weeks) using in vivo MRI acquisitions on a 7T Bruker ClinScan magnet. AßPP/PS1 mice present with rapid-onset cerebral ß-amyloidosis, and were compared with eight age-matched, wild-type control mice (C57Bl/6J) that do not develop Aß-deposition in brain. Data were analyzed with a novel automated voxel-based analysis that allowed mapping the entire brain for significant signal changes. In AßPP/PS1 mice, we found a significant decrease in T2 relaxation times in the deeper neocortical layers, caudate-putamen, thalamus, hippocampus, and cerebellum compared to wildtype controls. These changes were in line with the histological distribution of cerebral Aß plaques and activated microglia. Grey matter density did not differ between wild-type mice and AßPP/PS1 mice, consistent with a lack of neuronal loss in histological investigations. High-field MRI with automated mapping of T2 time changes may be a useful tool for the detection of plaque load in living transgenic animals, which may become relevant for the evaluation of amyloid lowering intervention effects in future studies.
