Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer's disease
Jee Hoon Roh, Hong Jiang, Mary Beth Finn, Floy R Stewart, Thomas E Mahan, John R Cirrito, Ashish Heda, B Joy Snider, Mingjie Li, Masashi Yanagisawa, Luis de Lecea, David M Holtzman, Jee Hoon Roh, Hong Jiang, Mary Beth Finn, Floy R Stewart, Thomas E Mahan, John R Cirrito, Ashish Heda, B Joy Snider, Mingjie Li, Masashi Yanagisawa, Luis de Lecea, David M Holtzman
Abstract
Age-related aggregation of amyloid-β (Aβ) is an upstream pathological event in Alzheimer's disease (AD) pathogenesis, and it disrupts the sleep-wake cycle. The amount of sleep declines with aging and to a greater extent in AD. Poor sleep quality and insufficient amounts of sleep have been noted in humans with preclinical evidence of AD. However, how the amount and quality of sleep affects Aβ aggregation is not yet well understood. Orexins (hypocretins) initiate and maintain wakefulness, and loss of orexin-producing neurons causes narcolepsy. We tried to determine whether orexin release or secondary changes in sleep via orexin modulation affect Aβ pathology. Amyloid precursor protein (APP)/Presenilin 1 (PS1) transgenic mice, in which the orexin gene is knocked out, showed a marked decrease in the amount of Aβ pathology in the brain with an increase in sleep time. Focal overexpression of orexin in the hippocampus in APP/PS1 mice did not alter the total amount of sleep/wakefulness and the amount of Aβ pathology. In contrast, sleep deprivation or increasing wakefulness by rescue of orexinergic neurons in APP/PS1 mice lacking orexin increased the amount of Aβ pathology in the brain. Collectively, modulation of orexin and its effects on sleep appear to modulate Aβ pathology in the brain.
© 2014 Roh et al.
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References
- Bero A.W., Yan P., Roh J.H., Cirrito J.R., Stewart F.R., Raichle M.E., Lee J.M., and Holtzman D.M.. 2011. Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nat. Neurosci. 14:750–756 10.1038/nn.2801
- Carter M.E., Yizhar O., Chikahisa S., Nguyen H., Adamantidis A., Nishino S., Deisseroth K., and de Lecea L.. 2010. Tuning arousal with optogenetic modulation of locus coeruleus neurons. Nat. Neurosci. 13:1526–1533 10.1038/nn.2682
- Chemelli R.M., Willie J.T., Sinton C.M., Elmquist J.K., Scammell T., Lee C., Richardson J.A., Williams S.C., Xiong Y., Kisanuki Y., et al. . 1999. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell. 98:437–451 10.1016/S0092-8674(00)81973-X
- Cirrito J.R., May P.C., O’Dell M.A., Taylor J.W., Parsadanian M., Cramer J.W., Audia J.E., Nissen J.S., Bales K.R., Paul S.M., et al. . 2003. In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-β metabolism and half-life. J. Neurosci. 23:8844–8853.
- Cirrito J.R., Kang J.E., Lee J., Stewart F.R., Verges D.K., Silverio L.M., Bu G., Mennerick S., and Holtzman D.M.. 2008. Endocytosis is required for synaptic activity-dependent release of amyloid-β in vivo. Neuron. 58:42–51 10.1016/j.neuron.2008.02.003
- de Lecea L., Kilduff T.S., Peyron C., Gao X., Foye P.E., Danielson P.E., Fukuhara C., Battenberg E.L., Gautvik V.T., Bartlett F.S. II, et al. . 1998. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl. Acad. Sci. USA. 95:322–327 10.1073/pnas.95.1.322
- Holtzman D.M., Goate A., Kelly J., and Sperling R.. 2011. Mapping the road forward in Alzheimer’s disease. Sci. Transl. Med. 3:114ps48 10.1126/scitranslmed.3003529
- Jankowsky J.L., Fadale D.J., Anderson J., Xu G.M., Gonzales V., Jenkins N.A., Copeland N.G., Lee M.K., Younkin L.H., Wagner S.L., et al. . 2004. Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase. Hum. Mol. Genet. 13:159–170 10.1093/hmg/ddh019
- Ju Y.E., and Holtzman D.M.. 2013. Sleep evaluation by actigraphy for patients with Alzheimer disease—reply. JAMA Neurol. 70:1074–1075 10.1001/jamaneurol.2013.3490
- Ju Y.E., Lucey B.P., and Holtzman D.M.. 2014. Sleep and Alzheimer disease pathology—a bidirectional relationship. Nat Rev Neurol. 10:115–119 10.1038/nrneurol.2013.269
- Kamenetz F., Tomita T., Hsieh H., Seabrook G., Borchelt D., Iwatsubo T., Sisodia S., and Malinow R.. 2003. APP processing and synaptic function. Neuron. 37:925–937 10.1016/S0896-6273(03)00124-7
- Kang J.E., Lim M.M., Bateman R.J., Lee J.J., Smyth L.P., Cirrito J.R., Fujiki N., Nishino S., and Holtzman D.M.. 2009. Amyloid-β dynamics are regulated by orexin and the sleep-wake cycle. Science. 326:1005–1007 10.1126/science.1180962
- Kim J., Castellano J.M., Jiang H., Basak J.M., Parsadanian M., Pham V., Mason S.M., Paul S.M., and Holtzman D.M.. 2009. Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A β clearance. Neuron. 64:632–644 10.1016/j.neuron.2009.11.013
- Koenigsknecht-Talboo J., Meyer-Luehmann M., Parsadanian M., Garcia-Alloza M., Finn M.B., Hyman B.T., Bacskai B.J., and Holtzman D.M.. 2008. Rapid microglial response around amyloid pathology after systemic anti-Aβ antibody administration in PDAPP mice. J. Neurosci. 28:14156–14164 10.1523/JNEUROSCI.4147-08.2008
- Matsuki T., Nomiyama M., Takahira H., Hirashima N., Kunita S., Takahashi S., Yagami K., Kilduff T.S., Bettler B., Yanagisawa M., and Sakurai T.. 2009. Selective loss of GABAB receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture. Proc. Natl. Acad. Sci. USA. 106:4459–4464 10.1073/pnas.0811126106
- Nir Y., Staba R.J., Andrillon T., Vyazovskiy V.V., Cirelli C., Fried I., and Tononi G.. 2011. Regional slow waves and spindles in human sleep. Neuron. 70:153–169 10.1016/j.neuron.2011.02.043
- Ooms S., Overeem S., Besse K., Rikkert M.O., Verbeek M., and Claassen J.A.. 2014. Effect of 1 night of total sleep deprivation on cerebrospinal fluid β-amyloid 42 in healthy middle-aged men: a randomized clinical trial. JAMA Neurol. 71:971–977 10.1001/jamaneurol.2014.1173
- Radde R., Bolmont T., Kaeser S.A., Coomaraswamy J., Lindau D., Stoltze L., Calhoun M.E., Jäggi F., Wolburg H., Gengler S., et al. . 2006. Aβ42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep. 7:940–946 10.1038/sj.embor.7400784
- Raichle M.E., MacLeod A.M., Snyder A.Z., Powers W.J., Gusnard D.A., and Shulman G.L.. 2001. A default mode of brain function. Proc. Natl. Acad. Sci. USA. 98:676–682 10.1073/pnas.98.2.676
- Roh J.H., Huang Y., Bero A.W., Kasten T., Stewart F.R., Bateman R.J., and Holtzman D.M.. 2012. Disruption of the sleep-wake cycle and diurnal fluctuation of β-amyloid in mice with Alzheimer’s disease pathology. Sci. Transl. Med. 4:150ra122 10.1126/scitranslmed.3004291
- Sperling R.A., Aisen P.S., Beckett L.A., Bennett D.A., Craft S., Fagan A.M., Iwatsubo T., Jack C.R. Jr, Kaye J., Montine T.J., et al. . 2011. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 7:280–292 10.1016/j.jalz.2011.03.003
- Spira A.P., Gamaldo A.A., An Y., Wu M.N., Simonsick E.M., Bilgel M., Zhou Y., Wong D.F., Ferrucci L., and Resnick S.M.. 2013. Self-reported sleep and β-amyloid deposition in community-dwelling older adults. JAMA Neurol. 70:1537–1543.
- Vlassenko A.G., Vaishnavi S.N., Couture L., Sacco D., Shannon B.J., Mach R.H., Morris J.C., Raichle M.E., and Mintun M.A.. 2010. Spatial correlation between brain aerobic glycolysis and amyloid-β (Aβ) deposition. Proc. Natl. Acad. Sci. USA. 107:17763–17767 10.1073/pnas.1010461107
- Vyazovskiy V.V., Olcese U., Lazimy Y.M., Faraguna U., Esser S.K., Williams J.C., Cirelli C., and Tononi G.. 2009. Cortical firing and sleep homeostasis. Neuron. 63:865–878 10.1016/j.neuron.2009.08.024
- Vyazovskiy V.V., Olcese U., Hanlon E.C., Nir Y., Cirelli C., and Tononi G.. 2011. Local sleep in awake rats. Nature. 472:443–447 10.1038/nature10009
- Xie L., Kang H., Xu Q., Chen M.J., Liao Y., Thiyagarajan M., O’Donnell J., Christensen D.J., Nicholson C., Iliff J.J., et al. . 2013. Sleep drives metabolite clearance from the adult brain. Science. 342:373–377 10.1126/science.1241224
- Yamada K., Holth J.K., Liao F., Stewart F.R., Mahan T.E., Jiang H., Cirrito J.R., Patel T.K., Hochgräfe K., Mandelkow E.M., and Holtzman D.M.. 2014. Neuronal activity regulates extracellular tau in vivo. J. Exp. Med. 211:387–393 10.1084/jem.20131685
- Yan P., Bero A.W., Cirrito J.R., Xiao Q., Hu X., Wang Y., Gonzales E., Holtzman D.M., and Lee J.M.. 2009. Characterizing the appearance and growth of amyloid plaques in APP/PS1 mice. J. Neurosci. 29:10706–10714 10.1523/JNEUROSCI.2637-09.2009
Source: PubMed