Choroid Plexus as a Target in Metal-induced Neurotoxicity

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 DESCRIPTION (provided by applicant): Loss of neurons in selective brain regions is the pathological characteristic of neurodegenerative diseases such as Parkinson disease (PD) and Alzheimer's disease (AD). Recent studies have provided evidence that neurogenesis in adult brain does occur and may mitigate adult neuronal loss by sustaining non‐motor function in PD and slowing cognitive deterioration and memory loss in AD. During adult neurogenesis, new neurons are generated from a proliferative niche called the subventricular zone (SVZ), which is nurtured by the cerebrospinal fluid (CSF) in brain ventricles. The SVZ provides neural stem/proliferating cells (NSPC) via the rostral migration stream (RMS) to the olfactory bulb (OB) and other brain regions. During the last funded period (2009‐2014), we have discovered that (i) the SVZ contains extraordinarily high amounts of copper (Cu) compared to other brain regions in adult rats; (ii) exposure to manganese (Mn) decreases Cu levels in SVZ; and (iii) the choroid plexus (CP), which produces the CSF, facilitates NSPC's proliferation and differentiation in SVZ. The central hypothesis to be tested in this competing renewal is that Cu plays a critical role in regulating neurogenesis in the SVZ; Mn exposure and subsequent accumulation in the CP disturbs Cu homeostasis in the CP, CSF and SVZ, leading to an arrested neurogenesis in adult brain. In Aim 1, we will establish the dose‐time‐response relationship of in vivo Mn exposure on neurogenesis. Studies in Aim 2 will reveal the mechanism of the high Cu accumulation in the SVZ and will determine if there is a threshold level above or below which Cu's modulation of stem cell's proliferation, migration and differentiation becomes compromised by Mn exposure. Furthermore, the Aim 3 experiments will focus on the endpoint toxicity of how Mn inhalation exposure retrospectively damages neurogenesis in the OB and SVZ. Finally in Aim 4, we will explore the factors secreted by the CP that have the direct effect on neurogenesis in the SVZ in the hope to establish a novel concept of the CP‐CSF‐SVZ axis in adult neurogenesis. This proposal continues our long‐term research goal, i.e., to explore the role of the CP and adjacent brain structures in metal‐induced neurotoxicities. Studies proposed in this application will establish a novel research area, i.e., toxicological implications of adult neurogenesis; will explore a novel mechanism of Mn‐induced parkinsonian disorder; and will define a novel relationship between CP and SVZ in adult neurogenesis. The outcomes will have a profound impact on our understanding of etiology of brain diseases.