Although alterations in the sympathetic nervous system (SNS) with age have been reported, and serious degenerative diseases of the autonomic nervous system such as multiple system atrophy are more likely to strike older people, connections between dysregulated adrenergic receptors and age-associated diseases and phenotypes have not been well studied. Two recent reports suggest that SNS may be more closely connected than previously appreciated. First, low nanomolar concentrations of Alzheimer's disease (AD)-associated Aβ42-amyloid oligomers alter signaling by SNS neurotransmitter norepinephrine (NE) to sufficiently activate kinase GSK3β to hyperphosphorylate tau, a key mediator of neurotoxicity in AD. Connecting beta-amyloid to tau in AD has been a key quest in understanding AD and developing therapeutics. The α2 adrenergic receptor inhibitory drug idazoxan reduces GSK3β activity and tau phosphorylation in AD mice with improved cognitive function, even in the presence of beta-amyloid deposits. In this study, SNS activation in the brain coupled with problematic Aβ42-amyloid oligomers result in serious consequences that can be ameliorated by reducing SNS signaling. A second example of the detrimental effects of increased SNS signaling is the premature graying of hair in response to stress. Secretion of NE resulting from stress causes differentiation of most hair pigment melanocyte stem cells (MeSCs) into melanocytes, rapidly depleting the hair follicle of pigment-producing cells as mature melanocytes undergo apoptosis and MeSCs are eventually eliminated. Blockade of NE SNS signaling preserves hair coloration in stressed animals. Increased SNS activation has serious apparently irreversible effects on homeostasis in both situations. Although neither report directly addresses aging, given that AD and the loss of hair pigmentation have strong age associations, it is of interest to better understand the role that SNS has in promoting age-associated phenotypes generally and determine if tuning the SNS through drug-mediated attenuation of SNS signaling may be of medical benefit.
Keywords: Alzheimer's disease; beta-amyloid; gray hair; sympathetic nervous system; tau.
β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade.Sci Transl Med. 2020 Jan 15;12(526):eaay6931. doi: 10.1126/scitranslmed.aay6931. Sci Transl Med. 2020. PMID: 31941827
Sympathetic nervous system activity in major depression. Basal and desipramine-induced alterations in plasma norepinephrine kinetics.Arch Gen Psychiatry. 1994 May;51(5):411-22. doi: 10.1001/archpsyc.1994.03950050071008. Arch Gen Psychiatry. 1994. PMID: 8179465 Clinical Trial.
Graying: gerontobiology of the hair follicle pigmentary unit.Exp Gerontol. 2001 Jan;36(1):29-54. doi: 10.1016/s0531-5565(00)00210-2. Exp Gerontol. 2001. PMID: 11162910 Review.
Active full-length DNA Aβ42 immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology.Alzheimers Res Ther. 2018 Nov 20;10(1):115. doi: 10.1186/s13195-018-0441-4. Alzheimers Res Ther. 2018. PMID: 30454039 Free PMC article.
Aging, graying and loss of melanocyte stem cells.Stem Cell Rev. 2007 Fall;3(3):212-7. doi: 10.1007/s12015-007-0028-0. Stem Cell Rev. 2007. PMID: 17917134 Review.