ABSTRACT
Stem cell transplantation therapy is currently in clinical trials for the treatment of ischemic stroke, and several beneficial aspects have been reported. Similarly, in Alzheimer's disease (AD), stem cell therapy is expected to provide an efficient therapeutic approach. Indeed, the intracerebral transplantation of stem cells reduced amyloid-ß (Aß) deposition and rescued memory deficits in AD model mice. Here, we show that intravenous transplantation of bone marrow-derived mononuclear cells (BMMCs) improves cognitive function in two different AD mouse models, DAL and APP mice, and prevents neurodegeneration. GFP-positive BMMCs were isolated from tibiae and femurs of 4-week-old mice and then transplanted intravenously into DAL and APP mice. Transplantation of BMMCs suppressed neuronal loss and restored memory impairment of DAL mice to almost the same level as in wild-type mice. Transplantation of BMMCs to APP mice reduced Aß deposition in the brain. APP mice treated with BMMCs performed significantly better on behavioral tests than vehicle-injected mice. Moreover, the effects were observed even with transplantation after the onset of cognitive impairment in DAL mice. Together, our results indicate that intravenous transplantation of BMMCs has preventive effects against the cognitive decline in AD model mice and suggest a potential therapeutic effect of BMMC transplantation therapy.
Subject(s)
Alzheimer Disease/therapy , Bone Marrow Transplantation/methods , Cognition Disorders/prevention & control , Leukocytes, Mononuclear/transplantation , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Alzheimer Disease/psychology , Animals , Bone Marrow Cells , Cognition Disorders/etiology , Disease Models, Animal , Female , Male , Maze Learning , Mice , Mice, Inbred C57BL , Mice, Transgenic , Models, Animal , Plaque, Amyloid/metabolismABSTRACT
Oxidative stress is known to play a prominent role in the onset and early stage progression of Alzheimer's disease (AD). For example, protein oxidation and lipid peroxidation levels are increased in patients with mild cognitive impairment. Here, we created a double-transgenic mouse model of AD to explore the pathological and behavioral effects of oxidative stress. Double transgenic (APP/DAL) mice were constructed by crossing Tg2576 (APP) mice, which express a mutant form of human amyloid precursor protein (APP), with DAL mice expressing a dominant-negative mutant of mitochondrial aldehyde dehydrogenase 2 (ALDH2), in which oxidative stress is enhanced. Y-maze and object recognition tests were performed at 3 and 6 months of age to evaluate learning and memory. The accumulation of amyloid plaques, deposition of phosphorylated-tau protein, and number of astrocytes in the brain were assessed histopathologically at 3, 6, 9, and 12-15 months of age. The life span of APP/DAL mice was significantly shorter than that of APP or DAL mice. In addition, they showed accelerated amyloid deposition, tau phosphorylation, and gliosis. Furthermore, these mice showed impaired performance on Y-maze and object recognition tests at 3 months of age. These data suggest that oxidative stress accelerates cognitive dysfunction and pathological insults in the brain. APP/DAL mice could be a useful model for exploring new approaches to AD treatment.
Subject(s)
Alzheimer Disease/metabolism , Alzheimer Disease/psychology , Amyloid/metabolism , Memory Disorders/psychology , Oxidative Stress , Aldehyde Dehydrogenase/genetics , Aldehyde Dehydrogenase, Mitochondrial , Alzheimer Disease/genetics , Amyloid beta-Protein Precursor/genetics , Animals , Brain/metabolism , Gliosis , Learning , Memory Disorders/genetics , Mice, Transgenic , Mitochondrial Proteins/genetics , Phosphorylation , tau Proteins/metabolismABSTRACT
The effect of a nonpeptide CC chemokine receptor antagonist, TAK-779, on ischemic brain injury resulting from 1-hour middle cerebral artery occlusion followed by 48-hour reperfusion was examined in ddY mice. On intracerebroventricular injection of vehicle or TAK-779, infarct volume in the vehicle-treated group was 44.2 +/- 13.2% of the contralateral hemispheric volume, and TAK-779 (25 and 250 ng/mouse) dose-dependently reduced the infarct volume to 35.0 +/- 12.2% and 31.1 +/- 12.9%, respectively. On intravenous injection, infarct volume in the vehicle-treated group was 32.0 +/- 16.1%, and TAK-779 (5 microg per 20 g body weight) significantly reduced this to 22.0 +/- 10.5%. The results showed for the first time that a nonpeptide chemokine receptor antagonist is protective against ischemic brain injury.
Subject(s)
Amides/therapeutic use , CCR5 Receptor Antagonists , Ischemic Attack, Transient/prevention & control , Quaternary Ammonium Compounds/therapeutic use , Amides/administration & dosage , Animals , Brain/pathology , Chemokine CCL4 , Immunohistochemistry , Injections, Intravenous , Injections, Intraventricular , Ischemic Attack, Transient/etiology , Ischemic Attack, Transient/pathology , Leukocytes/pathology , Macrophage Inflammatory Proteins/analysis , Male , Mice , Middle Cerebral Artery/surgery , Peroxidase/analysis , Quaternary Ammonium Compounds/administration & dosageABSTRACT
Excessively released glutamate is neurotoxic. Glutamate transporters maintain the extracellular level of glutamate by uptake into glia or neurons. We examined the role of GLT-1, a glial glutamate transporter, in brain damage resulting from transient focal ischemia in mice. Heterozygous gene deletion of GLT-1 significantly augmented brain swelling resulting from 1 h of middle cerebral artery occlusion and 24 h reperfusion. In addition, this gene deletion significantly increased brain water contents in ischemic hemisphere at 6 h after reperfusion. Moreover, intraperitoneal injection of dihydrokainate (10 mg/kg), a specific inhibitor of GLT-1, augmented brain swelling. These data suggest that GLT-1 limits brain edema resulting from ischemia.
