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Heterogeneity of mitral cell properties determined by the timing of neurogenesis - Supplement

由神经发生时间决定的二尖瓣细胞特性的异质性 - 补充

基本信息

批准号：
10286220
负责人：
Fumiaki Imamura
金额：
$ 40.88万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10286220
关键词：
Abeta clearance Address Age Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Amyloid beta-Protein Apolipoprotein E Area Atlases Attention Autophagocytosis Award Axon Binding Binding Proteins Brain Cells Consensus Dementia Deposition Development Electroporation Embryo Endocytosis Goals Heterogeneity Homeostasis Immunohistochemistry Impairment Integral Membrane Protein Knowledge LDL-Receptor Related Protein 1 Lateral Ligands Link Lipoprotein Receptor Memory Loss Metabolism Mitochondrial Proteins Molecular Mus Neurodegenerative Disorders Neurons Olfactory Cortex Olfactory Pathways Olfactory dysfunction Olfactory tract Parents Pathogenesis Pathologic Pattern Pilot Projects Plasmids Play Polymerase Chain Reaction Property Proteins Reporting Request for Applications Research Research Activity Research Support Reverse Transcription Role Short-Term Memory Signal Transduction Smell Perception Swelling Symptoms Testing Time Western Blotting Work abeta accumulation age related aged alpha 2-Glucoproteins common symptom experimental study falls glucose metabolism in utero information processing insight lipid metabolism mitral cell mouse model neurogenesis neuron development olfactory bulb postnatal receptor receptor mediated endocytosis small hairpin RNA spatiotemporal tau-1 uptake

项目摘要

ABSTRACT Impaired sense of smell is one of the early symptoms of Alzheimer’s disease (AD). Interestingly, brain areas involved in olfactory information processing, such as the olfactory bulb (OB), show amyloid-beta (Aβ) deposit and aggregation of phosphorylated tau at the very early stages of AD. However, the underlying mechanisms of olfactory dysfunction and the development of these AD pathological hallmarks in the olfactory area are still largely unknown. In the proposed research, we will focus on the functions of low-density lipoprotein receptor-related protein 1 (LRP1). LRP1 is a multifunctional transmembrane protein involved in receptor-mediated endocytosis and signal transduction. Since it binds to several molecules closely linked to AD development, LRP1 is considered as a key molecule in the pathogenesis of AD. Previous reports suggested that LRP1 is involved in the lipid and glucose metabolism, Aβ clearance, and propagation of phosphorylated tau between neurons. However, there is still no consensus about the role of LRP1 in AD pathogenesis. To address this unsolved problem, it is critical to accumulate knowledge about the functions of LRP1 in the normal brain. Through the experiments supported by the parent active R01 award, we have found that LRP1 is highly expressed by projection neurons, mitral and tufted cells, in the developing mouse OB, suggesting that LRP1 is involved in the development of OB projection neurons. We also have found that the non-presynaptic bead-like axonal swellings form along the mouse lateral olfactory tract (LOT), the bundle of mitral and tufted cell axons, and these swellings contain a mitochondrial protein and an autophagy receptor. Interestingly, the number and size of the swellings were increased in the LOT in an age-dependent manner. These findings suggest that the cellular metabolism of OB projection neurons differs between the aged and young mice. Given that LRP1 plays a critical role in cellular homeostasis, LRP1 may regulate the formation of axonal swellings in the LOT. As a first step to reveal the LRP1 function in the OB, we will examine whether LRP1 regulates the development and/or axonal swelling formation of OB projection neurons. We will address this research goal by pursuing the following two specific aims. Specific Aim 1 will determine the LRP1 expression pattern in the mouse OB at different ages from postnatal day 0 to 18 months old. Specific Aim 2 will examine the effects of LRP1 loss in the development and axonal swelling formation of OB projection neurons. The results will reveal the roles of LRP1 in the development of OB projection neurons and will provide us with significant insights into the LRP1 function in neuronal homeostasis. In this regard, the proposed subproject will advance our knowledge about the molecular mechanisms regulating the development of OB projection neurons and is an excellent pilot study to understand the contribution of LRP1 to AD pathogenesis and age-related olfactory dysfunction.

摘要