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Consequences of Noradrenergic Degeneration in the Novel TgF344-AD Rat Model

新型 TgF344-AD 大鼠模型中去甲肾上腺素能变性的后果

基本信息

批准号：
10581841
负责人：
LORI Lynn MCMAHON
金额：
$ 58.8万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581841
关键词：
AD transgenic mice APP-PS1 Adrenergic Agents Adrenergic Receptor Aging Agitation Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Amyloid beta-Protein Anxiety Attention Axon Back Behavior Biochemistry Biology Brain Brain region Cells Chemicals Chemosensitization Clinical Cognition Cognitive Cognitive deficits Control Locus Data Denervation Disease Disease Progression Distal Electrophysiology (science)Estradiol Female Fiber Fright Functional disorder Hippocampal Formation Hippocampus (Brain)Human Impairment Intervention Learning Lesion Light Link Literature Mainstreaming Masks Medial Memory Menopause Mental Health Modeling Mus Neurons Norepinephrine Outcome Ovarian hormone Pathologic Pathology Patients Perforant Pathway Pharmacology Phosphorylation Plasma Positioning Attribute Post-Translational Protein Processing Proestrus Prosencephalon Rattus Reporting Research Role Serine Sex Differences Slice Source Synapses Synaptic Transmission System Testing Therapeutic Therapeutic Intervention Threonine Transgenic Organisms Up-Regulation Woman Work abeta accumulation axonal degeneration basal forebrain beta-2 Adrenergic Receptors beta-adrenergic receptor cholinergic comorbid depression comorbidity density dentate gyrus emerging adult experience granule cell health knowledge human disease hyperphosphorylated tau improved innovation locus ceruleus structure male mouse model neglect nerve supply neuroinflammation neuronal excitability noradrenergic novel pre-clinical preservation prevent prodromal Alzheimer&apos s disease receptor function sex sexual dimorphism spatial memory synaptic function tau aggregation tau-1

项目摘要

Project Summary Noradrenergic (NA) input to hippocampus from locus coeruleus (LC), the sole supplier of NA innervation to forebrain, is required for acquisition and consolidation of spatial learning and memory and contextual fear behavior. The dentate gyrus (DG) contains the highest NA content, greatest NA fiber density, and largest expression of β1-and β2-adrenergic receptors (ARs) in the hippocampal formation, consistent with DG being a key region of modulatory control by LC. There is a rich literature dating back to the mid 1980’s showing a critical role for β-ARs in facilitating induction of both LTP and LTD at DG synapses depending upon the saliency of the experience. This heightened plasticity occurs simultaneous with heightened learning and memory, and both are prevented by loss of NA innervation or pharmacological blockade of β-ARs. Importantly, the LC in females has a larger volume, LC neurons have greater dendritic arbors, and at proestrus, when plasma estradiol levels are the highest, NA neuronal activity is decreased. The LC is the first brain region damaged in Alzheimer’s disease (AD), due to accumulation of hyper- phosphorylated tau (p-tau). The consequence of this pathology is greatly under-appreciated since transgenic AD mouse models do not recapitulate this feature of human disease. Fortunately, the novel TgF344-AD rat model has significant p-tau accumulation in LC and NA axon loss in hippocampus, permitting detailed studies of LC and NA system dysfunction on hippocampal synaptic transmission and learning and memory. Clearly, identifying strategies to prevent p-tau accumulation and LC damage is critical. The post-translational modification, O- GlcNAcylation, has been shown to do just this through competition with phosphorylation at key serine residues on p-tau that cause its accumulation. Using brain slice electrophysiology, we reported pathologically heightened LTP at medial perforant path synapses in dentate gyrus prior to CA1 synapses in both sexes. In recent data, we find heightened potentiation at medial perforant path synapses following pharmacological activation of β-ARs. This upregulation of β-AR function in the context NA fiber loss likely drives the heightened LTP and masks deficits in learning and memory early in the disease. The current proposal will test the hypothesis that hippocampal noradrenergic function in AD is impaired via aberrant excitability of LC-NA cells caused by progressive p-tau accumulation and through NA denervation, both of which will be worse in ovariectomized females and protected by O-GlcNAcylation. We will use a combination of electrophysiology in hippocampus and locus coeruleus, hippocampus-dependent behavior, pharmacology, biochemistry, and O-GlcNAc biology to test this innovative hypothesis. Outcomes will shed new light on the role of LC damage in AD, and will lay the ground work for therapeutic strategies targeting the LC and perhaps O-GlcNAcylation.

项目总结