Alzheimer's disease (AD) is the most common cause of dementia. There is compelling data that the amyloid- beta (Abeta) peptide plays a key early role in initiating disease pathogenesis. The progressive buildup of toxic forms of Abeta in the brain appears to ultimately lead to downstream events culminating in dementia. Since the concentration of soluble Abeta peptide is directly related to the probability that it will aggregate, determining what normally regulates Abeta levels in the brain will likely provide critical insights ino factors that initiate the AD pathological cascade. The investigators on this PPG proposal have found that synaptic activity is dynamically coupled with the release of the Abeta peptide in the extracellular space of the brain. Our labs have utilized mouse models of AD to discover some of the cellular mechanisms that link synaptic transmission and dynamic changes in Abeta levels in awake, behaving mice with confirmation in human studies. Abeta is dynamically regulated by the sleep-wake cycle and this regulation appears important in determining Abeta deposition later in life. The regulation of Abeta by the sleep-wake cycle may be tied to synaptic activity as brain interstitial fluid (ISF) levels of Abeta are directly coupled with synaptic activity both pre- and post-synapticall. A molecule likely involved in this coupling is LRP1, since APP endocytosis is required for a large component of Abeta generation and LRP1 influences APP endocytosis and Abeta generation. Our hypothesis is that synaptic activity influences both Abeta production and clearance in the brain and that over time this activity influences whether, where, and when Abeta aggregates into toxic species in the brain. In addition, we hypothesize that synaptic activity-mediated Abeta generation and release 1) is influenced by the sleep/wake cycle and molecules that regulate that cycle;2) occurs in part via post-synaptic stimulation of NMDA receptors via ERK signaling;and 3) is influenced by the LDL-receptor related protein-1 (LRP1) via its interactions with APP. We will combine unique techniques including in vivo protein microdialysis, 13C-labeled amino acid pulse chase labeling combined with mass spectrometry, and focal viral-mediated gene delivery with approaches that assess systems level network function, synaptic and molecular signaling, and cell biology.

Public Health Relevance

Alzheimer's disease is the most common cause of dementia and a major public health problem. The number of cases will likely double in the next 20 years without an effective treatment. Understanding the effects of brain networks, the sleep-wake cycle, and the synaptic, cellular and molecular mechanisms underlying Abeta regulation will provide novel insights into AD pathogenesis and potentially new treatment ideas.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS074969-03
Application #
8642679
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Corriveau, Roderick A
Project Start
2012-05-15
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
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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