ABSTRACT
SIRT1 induces cell survival and has shown neuroprotection against amyloid and tau pathologies in Alzheimer's disease (AD). However, protective effects against memory loss or the enhancement of cognitive functions have not yet been proven. We aimed to investigate the benefits induced by SIRT1 overexpression in the hippocampus of the AD mouse model 3xTg-AD and in control non-transgenic mice. A lentiviral vector encoding mouse SIRT1 or GFP, selectively transducing neurons, was injected into the dorsal CA1 hippocampal area of 4-month-old mice. Six-month overexpression of SIRT1 fully preserved learning and memory in 10-month-old 3xTg-AD mice. Remarkably, SIRT1 also induced cognitive enhancement in healthy non-transgenic mice. Neuron cultures of 3xTg-AD mice, which show traits of AD-like pathology, and neuron cultures from non-transgenic mice were also transduced with lentiviral vectors to analyze beneficial SIRT1 mechanisms. We uncovered novel pathways of SIRT1 neuroprotection through enhancement of cell proteostatic mechanisms and activation of neurotrophic factors not previously reported such as GDNF, present in both AD-like and healthy neurons. Therefore, SIRT1 may increase neuron function and resilience against AD.
Subject(s)
Cognition/physiology , Hippocampus/metabolism , Learning/physiology , Sirtuin 1/metabolism , Amyloid beta-Protein Precursor/metabolism , Animals , Disease Models, Animal , Hippocampus/drug effects , Male , Mice, Transgenic , Neurons/metabolism , Nootropic Agents/metabolismABSTRACT
AIMS: Glial cell-derived neurotrophic factor (GDNF) is emerging as a potent neurotrophic factor with therapeutic potential against a range of neurodegenerative conditions including Alzheimer's disease (AD). We assayed the effects of GDNF treatment in AD experimental models through gene-therapy procedures. METHODS: Recombinant lentiviral vectors were used to overexpress GDNF gene in hippocampal astrocytes of 3xTg-AD mice in vivo, and also in the MC65 human neuroblastoma that conditionally overexpresses the 99-residue carboxyl-terminal (C99) fragment of the amyloid precursor protein. RESULTS: After 6 months of overexpressing GDNF, 10-month-old 3xTg-AD mice showed preserved learning and memory, while their counterparts transduced with a green fluorescent protein vector showed cognitive loss. GDNF therapy did not significantly reduce amyloid and tau pathology, but rather, induced a potent upregulation of brain-derived neurotrophic factor that may act in concert with GDNF to protect neurons from atrophy and degeneration. MC65 cells overexpressing GDNF showed an abolishment of oxidative stress and cell death that was at least partially mediated by a reduced presence of intracellular C99 and derived amyloid ß oligomers. CONCLUSIONS: GDNF induced neuroprotection in the AD experimental models used. Lentiviral vectors engineered to overexpress GDNF showed to be safe and effective, both as a potential gene therapy and as a tool to uncover the mechanisms of GDNF neuroprotection, including cross talk between astrocytes and neurons in the injured brain.
Subject(s)
Alzheimer Disease/therapy , Genetic Therapy/methods , Glial Cell Line-Derived Neurotrophic Factor/therapeutic use , Alzheimer Disease/complications , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Amyloid beta-Protein Precursor/genetics , Animals , Cell Line, Tumor , Cognition Disorders/etiology , Cognition Disorders/therapy , Disease Models, Animal , Glial Cell Line-Derived Neurotrophic Factor/biosynthesis , Glial Cell Line-Derived Neurotrophic Factor/pharmacology , Hippocampus/metabolism , Humans , Lentivirus/genetics , Male , Maze Learning/physiology , Mice , Mice, Transgenic , Mutation/genetics , Neuroblastoma/pathology , Presenilin-1/genetics , Reactive Oxygen Species/metabolism , tau Proteins/geneticsABSTRACT
Postmenopausal women may be more vulnerable to cognitive loss and Alzheimer's disease (AD) than premenopausal women because of their deficiency in estrogens, in addition to their usually older age. Aerobic physical exercise has been proposed as a therapeutic approach for maintaining health and well-being in postmenopausal women, and for improving brain health and plasticity in populations at high risk for AD. To study the neuroprotective mechanisms of physical exercise in a postmenopausal animal model, we submitted previously ovariectomized, six-month old non-transgenic and 3xTg-AD mice to three months of voluntary exercise in a running wheel. At nine months of age, we observed lower grip strength and some exacerbation of the behavioral and psychological symptoms of dementia (BPSD)-like involving active exploratory activities. A similar major cognitive impairment was observed of ovariectomized 3xTg-AD mice in comparison with sham-operated 3xTg-AD mice. A reduction of bodily fitness and lack of retention of memory were observed in the ovariectomized non-transgenic mice. Physical exercise protected against all deleterious behaviors and normalized learning and memory. It also protected against body frailty, as expected. Analyses of hippocampal key markers of antioxidant and neuroplasticity signaling pathways, showed that ovariectomy impairs the activation of CREB through physical exercise. Furthermore, molecular and behavioral correlates suggested a central role of BDNF in the neuroprotection mediated by physical exercise therapy against apathy and memory loss induced by ovariectomy and the AD-genotype.
Subject(s)
Alzheimer Disease , Brain-Derived Neurotrophic Factor/physiology , Cytoprotection , Neurons/physiology , Physical Conditioning, Animal/physiology , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Alzheimer Disease/psychology , Amyloid beta-Protein Precursor/genetics , Animals , Cognition/physiology , Disease Models, Animal , Female , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neuroprotective Agents , Ovariectomy , Physical Conditioning, Animal/psychology , Presenilin-1/genetics , Signal Transduction , tau Proteins/geneticsABSTRACT
Physical exercise has become a potentially beneficial therapy for reducing neurodegeneration symptoms in Alzheimer's disease. Previous studies have shown that cognitive deterioration, anxiety and the startle response observed in 7-month-old 3xTg-AD mice were ameliorated after 6 months of free access to a running wheel. Also, alterations in synaptic response to paired-pulse stimulation were improved. The present study further investigated some molecular mechanisms underlying the beneficial effects of 6 months of voluntary exercise on synaptic plasticity in 7-month-old 3xTg-AD mice. Changes in binding parameters of [(3)H]-flunitrazepam to GABAA receptor and of [(3)H]-MK-801 to NMDA receptor in cerebral cortex of 3xTgAD mice were restored by voluntary exercise. In addition, reduced expression levels of NMDA receptor NR2B subunit were reestablished. The synaptic proteins synaptophysin and PSD-95 and the neuroprotective proteins GDNF and SIRT1 were downregulated in 3xTgAD mice and were recovered by exercise treatment. Overall, in this paper we highlight the fact that different interrelated mechanisms are involved in the beneficial effects of exercise on synaptic plasticity alterations in the 3xTg-AD mouse model.
Subject(s)
Alzheimer Disease/rehabilitation , Apoptosis Regulatory Proteins/metabolism , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Physical Conditioning, Animal/methods , Synapses/physiology , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Amyloid beta-Protein Precursor/genetics , Animals , Cerebral Cortex/drug effects , Disease Models, Animal , Dizocilpine Maleate/pharmacokinetics , Dose-Response Relationship, Drug , Excitatory Amino Acid Antagonists/pharmacokinetics , Flunitrazepam/pharmacokinetics , GABA Modulators/pharmacokinetics , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Humans , Mice , Mice, Transgenic , Presenilin-1/genetics , Protein Binding/drug effects , Receptors, N-Methyl-D-Aspartate/metabolism , Tritium/pharmacokineticsABSTRACT
Physical exercise is considered to exert a positive neurophysiological effect that helps to maintain normal brain activity in the elderly. Expectations that it could help to fight Alzheimer's disease (AD) were recently raised. This study analyzed the effects of different patterns of physical exercise on the 3xTg-AD mouse. Male and female 3xTg-AD mice at an early pathological stage (4-month-old) have had free access to a running wheel for 1 month, whereas mice at a moderate pathological stage(7-month-old) have had access either during 1 or 6 months. The non-transgenic mouse strain was used as a control. Parallel animal groups were housed in conventional conditions. Cognitive loss and behavioral and psychological symptoms of dementia (BPSD)-like behaviors were present in the 3xTg-AD mice along with alteration in synaptic function and ong-term potentiation impairment in vivo. Brain tissue showed AD-pathology and oxidative-related changes. Disturbances were more severe at the older age tested. Oxidative stress was higher in males but other changes were similar or higher in females. Exercise treatment ameliorated cognitive deterioration and BPSD-like behaviors such as anxiety and the startle response. Synaptic changes were partially protected by exercise. Oxidative stress was reduced. The best neuroprotection was generally obtained after 6 months of exercise in 7-month-old 3xTg-AD mice. Improved sensorimotor function and brain tissue antioxidant defence were induced in both 3xTg-AD and NonTg mice. Therefore, the benefits of aerobic physical exercise on synapse, redox homeostasis, and general brain function demonstrated in the 3xTg-AD mouse further support the value of this healthy life-style against neurodegeneration.
Subject(s)
Alzheimer Disease/rehabilitation , Exercise/physiology , Physical Therapy Modalities , Acoustic Stimulation , Age Factors , Alzheimer Disease/complications , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Animals , Body Weight/genetics , Brain/metabolism , Brain/pathology , Cognition Disorders/etiology , Cognition Disorders/prevention & control , Conditioning, Operant/physiology , Dark Adaptation/genetics , Disease Models, Animal , Electroencephalography , Enzyme-Linked Immunosorbent Assay , Excitatory Postsynaptic Potentials/genetics , Exploratory Behavior/physiology , Female , Glutathione/metabolism , Glutathione Disulfide/metabolism , Humans , Male , Maze Learning/physiology , Mice , Mice, Transgenic , Mutation/genetics , Neural Inhibition/genetics , Peptide Fragments/metabolism , Presenilin-1/genetics , Reflex, Startle/genetics , tau Proteins/geneticsABSTRACT
The 3xTg-AD mouse develops a progressive Alzheimer's disease- (AD-) like brain pathology that causes cognitive- and neuropsychiatric-like symptoms of dementia. Since its neuroimmunoendocrine axis is likewise impaired, this mouse is also useful for modelling complex age-related neurodegeneration. This study analyzed behavioral, physiological, neurochemical, pathological and immunoendocrine alterations in male and female 3xTg-AD mice and assayed the effects of a short therapy of forced physical exercise at the moderate pathology stage of 6 months of age. Gender effects were observed in most AD-related pathology and dysfunctions. Five weeks of treadmill training produced beneficial effects, such as the reduction of brain oxidative stress and GABA-A receptor dysfunction in males and improvement of sensorimotor function in females. In both sexes, exercise decreased the brain amyloid ß 42/40 ratio levels. The results highlight the importance of analyzing experimental therapies in both mouse model genders in order to improve our understanding of the disease and develop more appropriate therapies.
