. Melatonin Treatment Enhances Aβ Lymphatic Clearance in a Transgenic Mouse Model of Amyloidosis. Curr Alzheimer Res. 2018;15(7):637-642. PubMed.

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  1. Orexin and melatonin, the elephant in the room.

    The paper by Pappolla et al. brings attention to several important points regarding the mechanisms of amyloid accumulation: 

    1. According to conventional concepts of cerebral interstitial fluid (ISF) clearance, the ISF can drain via the olfactory nerve and cribiform plate into the cervical lymph nodes (Cserr, 1983). The identification of Aβ in the ISF has led to the assumption that amyloid is cleared into the peripheral lymphatic system. However, except for this paper and a prior study by the same investigators (Pappolla et al., 2014) there is no other published experimental data documenting that brain Aβ is actually cleared into the peripheral lymph nodes. This is a significant finding that must be confirmed by independent studies.
    2. Recent studies reported that Aβ levels in the ISF are regulated by the sleep-wake cycle in both humans and mice (Ju et al., 2014; Kang et al., 2009). Aβ in the ISF is higher during wakefulness and lower during sleep (Ju et al., 2014). In humans, circadian rhythm abnormalities associate tightly with amyloid accumulation (Musiek et al., 2018). Melatonin is involved in regulating the sleep-wake cycle and its levels are lower in Alzheimer’s disease (Liu et al., 1999). In addition to having anti-aggregatory and neuroprotective features, melatonin promotes sleep by inhibiting orexin neurons in the lateral hypothalamus (Sharma et al., 2018). Orexin is a hypothalamic neurotransmitter which produces wakefulness and reduces REM sleep. It has been demonstrated that early in the disease process, there is overexpression of orexinergic signaling, which in turns, alters the sleep-wake cycle and secondarily induces Aβ accumulation (Liguori, 2017). Therefore, the discovery that melatonin can enhance Aβ clearance through the lymphatic system may be significant to the mechanism of amyloid accumulation.

    Interestingly, orexin receptor antagonists are now readily available as sleep aids. The roles of melatonin and orexin receptor antagonists, individually or in combination, should thus be explored in prevention trials to delay the onset of cognitive impairment in preclinical Alzheimer’s disease. To date, no double-blind, placebo-controlled studies for AD prevention have been conducted using these readily available agents.

    References:

    . Flow of Brain Interstitial Fluid and Drainage into Cerebrospinal Fluid and Lymph. In: Ishii S., Nagai H., Brock M. (eds) Intracranial Pressure V. Springer, Berlin, Heidelberg. (1983)

    . Evidence for lymphatic Aβ clearance in Alzheimer's transgenic mice. Neurobiol Dis. 2014 Nov;71:215-9. Epub 2014 Aug 4 PubMed.

    . Sleep and Alzheimer disease pathology--a bidirectional relationship. Nat Rev Neurol. 2014 Feb;10(2):115-9. Epub 2013 Dec 24 PubMed.

    . Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science. 2009 Nov 13;326(5955):1005-7. PubMed.

    . Circadian Rest-Activity Pattern Changes in Aging and Preclinical Alzheimer Disease. JAMA Neurol. 2018 May 1;75(5):582-590. PubMed.

    . Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer's disease, and apolipoprotein E-epsilon4/4 genotype. J Clin Endocrinol Metab. 1999 Jan;84(1):323-7. PubMed.

    . Melatonin promotes sleep in mice by inhibiting orexin neurons in the perifornical lateral hypothalamus. J Pineal Res. 2018 Apr 14;:e12498. PubMed.

    . Orexin and Alzheimer's Disease. Curr Top Behav Neurosci. 2017;33:305-322. PubMed.

  2. This study is a significant contribution. It represents the culmination of research started in 1993, when Dr. Pappolla started a collaboration with me and Dr. Sambamurti in my laboratory. I trust that with this determined pursuit, the study will lead to a clinical trial to test efficacy in humans. 

    Melatonin has several properties relevant to Alzheimer’s disease. However, a clinical trial of melatonin to prevent or delay the onset of cognitive decline in preclinical AD has never been conducted. Data from several sources suggests that melatonin may be useful if used as a preventative agent, rather than to reverse the established disease. Here are some reasons why such a prevention study should be performed.

    Melatonin interacts in a structure-specific manner with Aβ, inhibiting the progressive formation of β-sheets and neurotoxic oligomers (Pappolla et al., 1998). In fact, this substance is the only endogenous inhibitor of Aβ aggregation. Its levels in CSF are markedly decreased in AD (Liu et al., 1999; Wu and Swaab, 2005). Recent meta-analyses of melatonin trials performed during the MCI stage of the disease have shown slowing of cognitive decline (Cardinali et al., 2011; Cardinali et al., 2012). 

    There is a circadian pattern of Aβ production that is altered in preclinical AD in a manner which may contribute to amyloid accumulation (Kang et al., 2009; Musiek et al., 2018). It has been theorized that early treatment of sleep disorders associated with preclinical AD may potentially delay the onset of cognitive decline (Musiek et al., 2018; Liguori, 2017). In this regard, melatonin is key in resynchronizing circadian rhythms abnormalities such as those present in AD.

    Melatonin is an immunomodulatory substance. It acts as a stimulator of the innate immunity under basal or immunosuppressive conditions, i.e., immuno-senescence (Carrillo-Vico et al., 2013). This is relevant to AD, considering the emerging role of the innate immunity in this disorder (Scholtzova et al., 2017). 

    Oxidative damage is pervasive in brains with AD (Pappolla et al., 1992; Smith et al., 1996). Melatonin prevents oxidative injury and neuronal death in several paradigms relevant to AD (Pappolla et al., 1997). Since these initial reports were published two decades ago, these findings have been confirmed in numerous independent studies in in vitro and in vivo models of AD (Shukla et al., 2017). 

    Finally, this paper provides a simple, yet important confirmation of what has been suspected for some time; e.g., that Aβ is cleared trough the lymphatic system. Historically, various pathways have been proposed to participate in the clearance of metabolic products from the brain. These include clearance through the cribiform plate, cranial and spinal nerves, meningeal lymphatic vessels, and paravascular pathways (glymphatic system). Several investigators have theorized that accumulation of Aβ may reflect decreased clearance through these routes. However, little information was available to directly link brain Aβ peripheral lymph nodes. The data presented in this study highlights an important pathway for amyloid clearance that warrants further examination.

    References:

    . Inhibition of Alzheimer beta-fibrillogenesis by melatonin. J Biol Chem. 1998 Mar 27;273(13):7185-8. PubMed.

    . Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer's disease, and apolipoprotein E-epsilon4/4 genotype. J Clin Endocrinol Metab. 1999 Jan;84(1):323-7. PubMed.

    . The human pineal gland and melatonin in aging and Alzheimer's disease. J Pineal Res. 2005 Apr;38(3):145-52. PubMed.

    . The use of chronobiotics in the resynchronization of the sleep/wake cycle. Therapeutical application in the early phases of Alzheimer's disease. Recent Pat Endocr Metab Immune Drug Discov. 2011 May;5(2):80-90. PubMed.

    . Therapeutic application of melatonin in mild cognitive impairment. Am J Neurodegener Dis. 2012;1(3):280-91. PubMed.

    . Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science. 2009 Nov 13;326(5955):1005-7. PubMed.

    . Circadian Rest-Activity Pattern Changes in Aging and Preclinical Alzheimer Disease. JAMA Neurol. 2018 May 1;75(5):582-590. PubMed.

    . Orexin and Alzheimer's Disease. Curr Top Behav Neurosci. 2017;33:305-322. PubMed.

    . Melatonin: buffering the immune system. Int J Mol Sci. 2013 Apr 22;14(4):8638-83. PubMed.

    . Innate Immunity Stimulation via Toll-Like Receptor 9 Ameliorates Vascular Amyloid Pathology in Tg-SwDI Mice with Associated Cognitive Benefits. J Neurosci. 2017 Jan 25;37(4):936-959. PubMed.

    . Immunohistochemical evidence of oxidative [corrected] stress in Alzheimer's disease. Am J Pathol. 1992 Mar;140(3):621-8. PubMed.

    . Oxidative posttranslational modifications in Alzheimer disease. A possible pathogenic role in the formation of senile plaques and neurofibrillary tangles. Mol Chem Neuropathol. 1996 May-Aug;28(1-3):41-8. PubMed.

    . Melatonin prevents death of neuroblastoma cells exposed to the Alzheimer amyloid peptide. J Neurosci. 1997 Mar 1;17(5):1683-90. PubMed.

    . Mechanisms of Melatonin in Alleviating Alzheimer's Disease. Curr Neuropharmacol. 2017 Mar 13; PubMed.

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