(See insti-uctions): Most neurodegenerative diseases, including Alzheimer's disease (AD), are disorders of protein aggregation in which specific proteins that are normally soluble, aggregate in the intra or extracellular space of the brain. In AD, a key factor that regulates whether an aggregation prone protein goes on to misfold is its concentration. Studies have shown that synaptic activity due to both presynaptic arid postsynaptic factors is coupled with the neuronal release of amyloid-B (AB). This suggests that understanding how integrated synaptic and network activity regulate both AB and potentially other proteins involved in neurodegenerative disease, may provide novel insights into pathogenesis. We found that in the brain interstitial fluid of mice (ISF), AP levels are dynamically and positively associated with the number of minutes awake per hour. Pharmacological studies showed that exogenous and endogenous orexin modulates both wakefulness and AB levels. Chronic sleep deprivation markedly increased and an orexin-receptor antagonist decreased AB deposition in APP Tg mouse models. Our preliminary data show that in ISF AB levels as well as measures of brain metabolic/synaptic activity predict how much AB deposition will occur in specific brain regions. Based on these results, we hypothesize that differences in brain metabolic/synaptic activity between brain regions regulate ISF AB levels and that the sleep/wake state regulates both soluble AB levels and ultimately AB deposition via effects on synaptic activity.
The specific aims are: 1) To dynamically measure the levels of ISF AB, molecules linked with synaptic activity such as lactate, molecules controlling wakefulness (orexin), and sleep (growth hormone releasing hormone-GHRH) by in vivo microdialysis in different brain regions with aging. 2) To determine the effects of genetic and pharmacological manipulation of orexin and GHRH signaling as well as effects of endogenous NMDA receptor activation, ERK signaling, and LRP1 on ISF AB fluctuations and the sleep/wake cycle in collaboration with projects 2 and 3. 3) To determine the relationship between mean sleep/wake time, other sleep features, and AD biomarkers (amyloid imaging, CSF AB and tau) in an ongoing study of cognitively normal humans (the adult children study) 45-75 years of age.

Public Health Relevance

Alzheimer's disease (AD) is the most common cause of dementia. There is no effective treatment that slows the progression of the disease. This project will assist in uncovering the relationship between normal processing of information in the brain (syaptic activity), the sleep/wake cycle, and the onset of AD changes in the brain. It has the possibility of revealing new potential avenues for treatment.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Saint Louis
United States
Zip Code
Liao, Fan; Zhang, Tony J; Mahan, Thomas E et al. (2015) Effects of growth hormone-releasing hormone on sleep and brain interstitial fluid amyloid-? in an APP transgenic mouse model. Brain Behav Immun 47:163-71
Lim, Miranda M; Gerstner, Jason R; Holtzman, David M (2014) The sleep-wake cycle and Alzheimer's disease: what do we know? Neurodegener Dis Manag 4:351-62
Shinohara, Mitsuru; Fujioka, Shinsuke; Murray, Melissa E et al. (2014) Regional distribution of synaptic markers and APP correlate with distinct clinicopathological features in sporadic and familial Alzheimer's disease. Brain 137:1533-49
Medway, Christopher W; Abdul-Hay, Samer; Mims, Tynickwa et al. (2014) ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer's disease. Mol Neurodegener 9:11
Tai, Leon M; Mehra, Shipra; Shete, Varsha et al. (2014) Soluble apoE/A? complex: mechanism and therapeutic target for APOE4-induced AD risk. Mol Neurodegener 9:2
Liu, Chia-Chen; Tsai, Chih-Wei; Deak, Ferenc et al. (2014) Deficiency in LRP6-mediated Wnt signaling contributes to synaptic abnormalities and amyloid pathology in Alzheimer's disease. Neuron 84:63-77
Zhao, Jing; Fu, Yuan; Liu, Chia-Chen et al. (2014) Retinoic acid isomers facilitate apolipoprotein E production and lipidation in astrocytes through the retinoid X receptor/retinoic acid receptor pathway. J Biol Chem 289:11282-92
Martínez-Morillo, Eduardo; Hansson, Oskar; Atagi, Yuka et al. (2014) Total apolipoprotein E levels and specific isoform composition in cerebrospinal fluid and plasma from Alzheimer's disease patients and controls. Acta Neuropathol 127:633-43
Kanekiyo, Takahisa; Xu, Huaxi; Bu, Guojun (2014) ApoE and A? in Alzheimer's disease: accidental encounters or partners? Neuron 81:740-54
Ju, Yo-El S; Lucey, Brendan P; Holtzman, David M (2014) Sleep and Alzheimer disease pathology--a bidirectional relationship. Nat Rev Neurol 10:115-9

Showing the most recent 10 out of 15 publications