Norepinephrine May Oppose Other Neuromodulators to Impact Alzheimer’s Disease

Abstract

While much of biomedical research since the middle of the twentieth century has focused on molecular pathways inside the cell, there is increasing evidence that extracellular signaling pathways are also critically important in health and disease. The neuromodulators norepinephrine (NE), serotonin (5-hydroxytryptamine, 5HT), dopamine (DA), acetylcholine (ACH), and melatonin (MT) are extracellular signaling molecules that are distributed throughout the brain and modulate many disease processes. The effects of these five neuromodulators on Alzheimer’s disease (AD) are briefly examined in this paper, and it is hypothesized that each of the five molecules has a u-shaped (or Janus-faced) dose-response curve, wherein too little or too much signaling is pathological in AD and possibly other diseases. In particular it is suggested that NE is largely functionally opposed to 5HT, ACH, MT, and possibly DA in AD. In this scenario, physiological “balance” between the noradrenergic tone and that of the other three or four modulators is most healthy. If NE is largely functionally opposed to other prominent neuromodulators in AD, this may suggest novel combinations of pharmacological agents to counteract this disease. It is also suggested that the majority of cases of AD and possibly other diseases involve an excess of noradrenergic tone and a collective deficit of the other four modulators.

Pathogenesis of (smoking-related) non-communicable diseases—Evidence for a common underlying pathophysiological pattern

“…Finally, overactivation of the SNS has been implicated in the development of AD. NE is thought to be functionally largely opposed to the neuromodulators serotonin, dopamine, acetylcholine and melatonin, which are distributed throughout the brain and modulate many processes in the pathophysiology underlying AD ( Fitzgerald, 2021 ). ( Limitation: see discussion ).…”

The role of the locus coeruleus/norepinephrine system in the pathogenesis of neurodegenerative disorders: An update

“…Interestingly, patients exposed to beta-blockers appear to have a lower incidence of dementia [31], while their role in Parkinson's disease is more controversial [32]. It has been recently suggested that the development of amyloid plaques and locus coeruleus degeneration are compensatory processes in response to long-term elevated noradrenergic signalling [33].…”