Project 2: Astrocyte-related molecular mechanisms underlying altered neuronal plasticitv in Down syndrome The goal of this project is to understand the molecular mechanisms associated with abnormal astrocyte function and their role in altered structural and functional plasficity in the Down's syndrome (DS) brain. Astrocytes are critical regulators of neuronal stem cells (NSCs) proliferation and differentiafion as well as dendritic spine development and synaptogenesis. We found metabolic deficits in DS astrocytes directly associated with reduced NSCs viability and aberrant spine formation. To investigate the molecular pathways associated with abnormal astrocyte function and its role in DS altered structural and functional neuroplasticity we propose: 1. To identify the molecular alterations in OS astrocytes responsible for impaired NSCs neurogenesis and spine pathology. We will define the role of intracellular AU and mitochondrial dysfunction in astrocyte secretory deficits, and the role of reduced APPs and thrombospondin 1 (TSP-1) secrefion in NSCs and spine pathology. 2. To analyze the effectiveness of mitochondrial cofactors and B-secretase inhibitors to prevent or revert DS astrocyte secretory deficits and concomitant NSCs and spine alterations. 3. A) To study the relation between astrocyte alterations, neurogenesis and spine anomalies in DS brains. We will generate normative data on the associafion between astrocyte alterations and NSCs and spine deficits in DS individuals. B) To assess the usefulness of TSP-1 levels in CSF and plasma as a biomarker of AD. We propose to perform preliminary studies to evaluate the usefulness of TSP-1 levels in plasma and CSF as a biomarker of AD in sporadic AD and DS+AD pafients. We will take advantage of our extensive experience culturing primary human nerve cells derived from fetal brain tissue. NSCs cultures in the form of neurospheres, pure astrocyte cultures, and cocultures of rat hippocampal neurons growing on top of human astrocytes (normal and DS) will be utilized for aims 1 and 2.
Aim 3 will utilize post-mortem brain samples and CSF and plasma samples provided by the Neuropathology Core. The Stafistical Core will provide feedback in all statistical procedures.

Public Health Relevance

These experiments will gather a wealth of information on novel aspects of DS structural and functional plasticity, which may be closely associated with the early and rapid transition to AD that occurs in most individuals with DS. We expect to identify novel therapeutic targets to treat neurodegeneration and cognitive decline not only in older DS individuals but also in the larger population affected by sporadic AD.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Specialized Center (P50)
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Special Emphasis Panel (ZAG1-ZIJ-4)
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University of California Irvine
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Katsumata, Yuriko; Nelson, Peter T; Ellingson, Sally R et al. (2017) Gene-based association study of genes linked to hippocampal sclerosis of aging neuropathology: GRN, TMEM106B, ABCC9, and KCNMB2. Neurobiol Aging 53:193.e17-193.e25
Brenowitz, Willa D; Keene, C Dirk; Hawes, Stephen E et al. (2017) Alzheimer's disease neuropathologic change, Lewy body disease, and vascular brain injury in clinic- and community-based samples. Neurobiol Aging 53:83-92
Shelton, Lindsey B; Baker, Jeremy D; Zheng, Dali et al. (2017) Hsp90 activator Aha1 drives production of pathological tau aggregates. Proc Natl Acad Sci U S A 114:9707-9712
Moga, Daniela C; Abner, Erin L; Wu, Qishan et al. (2017) Bladder antimuscarinics and cognitive decline in elderly patients. Alzheimers Dement (N Y) 3:139-148
Stark, Shauna M; Reagh, Zachariah M; Yassa, Michael A et al. (2017) What's in a context? Cautions, limitations, and potential paths forward. Neurosci Lett :
Sennik, Simrin; Schweizer, Tom A; Fischer, Corinne E et al. (2017) Risk Factors and Pathological Substrates Associated with Agitation/Aggression in Alzheimer's Disease: A Preliminary Study using NACC Data. J Alzheimers Dis 55:1519-1528
Chang, Timothy S; Teng, Edmond; Elashoff, David et al. (2017) Optimizing Effect Sizes With Imaging Enrichment and Outcome Choices for Mild Alzheimer Disease Clinical Trials. Alzheimer Dis Assoc Disord 31:19-26
Abud, Edsel M; Ramirez, Ricardo N; Martinez, Eric S et al. (2017) iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases. Neuron 94:278-293.e9
Kim, Julia; Schweizer, Tom A; Fischer, Corinne E et al. (2017) The Role of Cerebrovascular Disease on Cognitive and Functional Status and Psychosis in Severe Alzheimer's Disease. J Alzheimers Dis 55:381-389
Neu, Scott C; Pa, Judy; Kukull, Walter et al. (2017) Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis. JAMA Neurol 74:1178-1189

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