The Danger of Being Too Sympathetic: Norepinephrine in Alzheimer's Disease and Graying of Hair

Abstract

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 Ab42-amyloid oligomers alter signaling by SNS neurotransmitter norepinephrine (NE) to sufficiently activate kinase GSK3b 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 a 2 adrenergic receptor inhibitory drug idazoxan reduces GSK3b activity and tau phosphorylation in AD mice with improved cognitive function, even in the presence of betaamyloid deposits. In this study, SNS activation in the brain coupled with problematic Ab42-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.

Role of Amine Neurotransmitters and Their Receptors in Skin Pigmentation: Therapeutic Implication

“…Blocking NE sympathetic nerve system (SNS) signals preserves hair pigmentation in stressed animals. Increased SNS activation has a severe irreversible effect on homeostasis in greying of hair and Alzheimer’s disease [ 132 ].…”

Irradiation-induced hair graying in mice: an experimental model to evaluate the effectiveness of interventions targeting oxidative stress, DNA damage prevention, and cellular senescence

“…While hair graying is predominantly associated with chronological aging, there is considerable variation, both inter-individual and based on genetic background, in the onset and progression of graying [5,6]. Hair graying is a multifaceted process influenced by a combination of genetic, environmental, and age-related factors [7][8][9][10][11][12].…”

The biology of human hair greying

“…This is not least because the study of greying permits one to observe and interrogate gerontobiology of a uniquely accessible and experimentally tractable human mini‐organ found throughout the human integument. Moreover, an increasing number of animal and human studies have identified grey hair as an age‐independent predictor of serious extracutaneous pathology, including Alzheimer's disease (Mendelsohn & Larrick, 2020), Parkinson's disease (Jucevičiūtė et al ., 2019) and cardiovascular disease (Elfaramawy et al ., 2018), raising suspicion that hair greying may indeed act as an important indicator of systemic ageing‐associated pathology. As we grow closer to explaining this poorly understood phenomenon, it is timely to revisit critically what is known about the biology of hair greying today.…”