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

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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.