Targeting the Septohippocampal Circuit in Alzheimer's disease

靶向治疗阿尔茨海默病的中隔海马回路

基本信息

批准号：
9911267
负责人：
Connor Wander
金额：
$ 3.39万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2020-09-08 至 2021-08-04
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9911267
关键词：
3xTg-AD mouse Address Adverse effects Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapy Alzheimer’s disease biomarker Amyloid Amyloid beta-Protein Amyloid deposition Atrophic Axon Behavioral Biochemistry Brain Cell Density Cell Survival Chronic Clinical Clozapine Cognition Cognitive Cognitive deficits Disease Disease Progression Equilibrium Etiology Exposure to FDA approved Functional disorder Gliosis Glutamates Goals Hippocampus (Brain)Impairment Interneurons Intervention Knowledge Learning Life MAPT gene Mainstreaming Measures Medial Memantine Memory Memory impairment Mood Disorders Moods Morphology Mus Neurodegenerative Disorders Neurons Output Oxides Pathogenesis Pathologic Patient Care Patients Phenotype Population Prosencephalon Recovery Reporting Resolution Role Seizures Senile Plaques Stains Structure Symptoms Synapses Testing Therapeutic Theta Rhythm Training United States Viral abeta accumulation adult neurogenesis age related neurodegeneration aged basal forebrain burnout cholinergic cognitive function confocal imaging cost critical period density dentate gyrus design designer receptors exclusively activated by designer drugs effective therapy efficacy testing excitotoxicity experimental study gamma-Aminobutyric Acid inhibitory neuron insight mouse model nerve stem cell nervous system disorder neurogenesis neurotransmission normal aging novel novel therapeutic intervention novel therapeutics preservation productivity loss protein aggregation septohippocampal tau Proteins tau aggregation theories tool transmission process β-amyloid burden

项目摘要

PROJECT SUMMARY Alzheimer’s disease is characterized by pathological protein aggregates comprised of β-amyloid plaques and tau neurofibrillary tangles. Mainstream hypotheses highlight synaptic dysfunction and eventual neuronal atrophy as culprits for symptoms such as mood disorders, cognitive function, and impaired spatial learning and memory. The shortage of effective treatments highlights the gap in etiologic understanding of AD progression. While deficits in glutamatergic neurotransmission and atrophy of cholinergic forebrain neurons have been extensively studied, GABAergic transmission remains poorly understood in the context of AD. A key subpopulation of GABAergic neurons in the medial septum (MS-GABA) project exclusively to the hippocampus where they contact local inhibitory interneurons to support theta rhythm, spatial learning and memory, and adult neurogenesis. MS-GABA circuit dysfunction and degeneration is commonly observed in mouse models but has not yet been investigated in the 3xtg-AD line, thought to closely mimic AD progression. Circuit manipulation studies are emergent therapeutic strategies in neurological disorders. Therefore, we propose the use of chemogenetics to modulate the activity of the MS-GABA circuit in AD. We expect early MS-GABA stimulation to rebalance glutamate and GABA within the hippocampus of 3xtg-AD mice and expect recovery in spatial learning and memory deficits. These studies will facilitate identification of critical periods in prodromal stages of AD and test a novel therapeutic intervention strategy during these stages.

项目概要阿尔茨海默病的特征是由 β-淀粉样蛋白组成的病理性蛋白质聚集体斑块和 tau 神经原纤维缠结是突触功能障碍的主流假说。最终神经元萎缩，成为情绪障碍、认知障碍等症状的罪魁祸首功能、空间学习和记忆受损缺乏有效的治疗方法。突显了对 AD 进展病因学理解的差距，而谷氨酸能缺陷。胆碱能前脑神经元的神经传递和萎缩已被广泛研究， GABA 能传播在 AD 的背景下仍然知之甚少。内侧隔膜中的 GABA 能神经元 (MS-GABA) 专门投射到海马体他们在那里联系局部抑制性中间神经元以支持 theta 节律、空间学习和 MS-GABA 回路功能障碍和退化是常见的。在小鼠模型中观察到，但尚未在 3xtg-AD 系中进行研究，认为密切模拟 AD 进展的研究是新兴的治疗策略。因此，我们建议使用化学遗传学来调节。 AD 中 MS-GABA 回路的活性我们预计早期 MS-GABA 刺激会重新平衡。 3xtg-AD 小鼠海马内的谷氨酸和 GABA 并预计空间恢复这些研究将有助于识别学习和记忆缺陷的关键时期。 AD 的前驱阶段并在这些阶段测试一种新的治疗干预策略。