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 #
5P01NS074969-03
Application #
8642681
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
$207,467
Indirect Cost
$50,625
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Liu, Chia-Chen; Zhao, Na; Yamaguchi, Yu et al. (2016) Neuronal heparan sulfates promote amyloid pathology by modulating brain amyloid-β clearance and aggregation in Alzheimer's disease. Sci Transl Med 8:332ra44
Fisher, Jonathan R; Wallace, Clare E; Tripoli, Danielle L et al. (2016) Redundant Gs-coupled serotonin receptors regulate amyloid-β metabolism in vivo. Mol Neurodegener 11:45
Yamazaki, Yu; Baker, Darren J; Tachibana, Masaya et al. (2016) Vascular Cell Senescence Contributes to Blood-Brain Barrier Breakdown. Stroke 47:1068-77
Tachibana, Masaya; Shinohara, Mitsuru; Yamazaki, Yu et al. (2016) Rescuing effects of RXR agonist bexarotene on aging-related synapse loss depend on neuronal LRP1. Exp Neurol 277:1-9
Shinohara, Mitsuru; Kanekiyo, Takahisa; Yang, Longyu et al. (2016) APOE2 eases cognitive decline during Aging: Clinical and preclinical evaluations. Ann Neurol :
Sakae, Nobutaka; Liu, Chia-Chen; Shinohara, Mitsuru et al. (2016) ABCA7 Deficiency Accelerates Amyloid-β Generation and Alzheimer's Neuronal Pathology. J Neurosci 36:3848-59
Yuede, Carla M; Lee, Hyo; Restivo, Jessica L et al. (2016) Rapid in vivo measurement of β-amyloid reveals biphasic clearance kinetics in an Alzheimer's mouse model. J Exp Med 213:677-85
Ju, Yo-El S; Finn, Mary Beth; Sutphen, Courtney L et al. (2016) Obstructive sleep apnea decreases central nervous system-derived proteins in the cerebrospinal fluid. Ann Neurol 80:154-9
Shinohara, Mitsuru; Murray, Melissa E; Frank, Ryan D et al. (2016) Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer's disease. Acta Neuropathol 132:225-34
Fu, Yuan; Zhao, Jing; Atagi, Yuka et al. (2016) Apolipoprotein E lipoprotein particles inhibit amyloid-β uptake through cell surface heparan sulphate proteoglycan. Mol Neurodegener 11:37

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