Reducing levels of amyloid-B, the peptide that accumulates and causes Alzheimer's disease, is the most likely method to treat or prevent this disease. Our preliminary data demonstrates that postsynaptic signaling mechanisms, mainly through NMDA and orexin receptors, can dramatically reduce AB production and levels. We propose that both of these neurotransmitter systems activate substantially different signaling cascades that eventually converge on the extracellular-regulated kinase (ERK) signaling pathway. Activation of the ERK signaling cascade rapidly and dramatically reduces AB levels in vivo. This proposal will determine the cellular pathways that link these neurotransmitter receptors to ERK and AB metabolism. Understanding these pathways will provide insight into factors that contribute to disease risk as well as provide new pathways that could be targeted for therapeutic inten/enfion to treat AD.

Public Health Relevance

Reducing levels of amyloid-B (AB), the peptide that accumulates and causes Alzheimer's disease, is the most likely method to treat or prevent this disease. Our preliminary data demonstrates that certain neurotransmitter receptors can reduce AP levels in living mice. This proposal will determine the cellular pathways that link these receptors to Ap metabolism. This could lead to new avenues for therapeutic intervention

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS074969-02
Application #
8467072
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$202,831
Indirect Cost
$49,495
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Wojtas, Aleksandra M; Kang, Silvia S; Olley, Benjamin M et al. (2017) Loss of clusterin shifts amyloid deposition to the cerebrovasculature via disruption of perivascular drainage pathways. Proc Natl Acad Sci U S A 114:E6962-E6971
Zheng, Honghua; Jia, Lin; Liu, Chia-Chen et al. (2017) TREM2 Promotes Microglial Survival by Activating Wnt/?-Catenin Pathway. J Neurosci 37:1772-1784
Kang, S S; Ren, Y; Liu, C-C et al. (2017) Lipocalin-2 protects the brain during inflammatory conditions. Mol Psychiatry :
Liu, Chia-Chen; Hu, Jin; Zhao, Na et al. (2017) Astrocytic LRP1 Mediates Brain A? Clearance and Impacts Amyloid Deposition. J Neurosci 37:4023-4031
Czirr, Eva; Castello, Nicholas A; Mosher, Kira I et al. (2017) Microglial complement receptor 3 regulates brain A? levels through secreted proteolytic activity. J Exp Med 214:1081-1092
Holth, Jerrah; Patel, Tirth; Holtzman, David M (2017) Sleep in Alzheimer's Disease - Beyond Amyloid. Neurobiol Sleep Circadian Rhythms 2:4-14
Ju, Yo-El S; Ooms, Sharon J; Sutphen, Courtney et al. (2017) Slow wave sleep disruption increases cerebrospinal fluid amyloid-? levels. Brain 140:2104-2111
Zhong, Li; Chen, Xiao-Fen; Wang, Tingting et al. (2017) Soluble TREM2 induces inflammatory responses and enhances microglial survival. J Exp Med 214:597-607
Zhong, Li; Zhang, Zhen-Lian; Li, Xinxiu et al. (2017) TREM2/DAP12 Complex Regulates Inflammatory Responses in Microglia via the JNK Signaling Pathway. Front Aging Neurosci 9:204
Liu, Chia-Chen; Zhao, Na; Fu, Yuan et al. (2017) ApoE4 Accelerates Early Seeding of Amyloid Pathology. Neuron 96:1024-1032.e3

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