Degeneration of the locus ceruleus (LC), a brainstem region that supplies norepinephrine, has long been implicated in Alzheimer disease (Iversen et al., 1983; Bondareff et al., 1987; Grudzien et al., 2007). Now, a report in this week’s PNAS Early Edition offers a mechanism for how loss of LC neurons could contribute to AD pathogenesis. The data suggest that LC-supplied norepinephrine helps regulate microglial activities that keep amyloid pathology at bay. “If you have a drop in norepinephrine levels, this acts as a motor for disease progression because it facilitates the inflammatory response toward Aβ deposition and impairs the ability of microglia to get rid of these deposits. It's a dual effect,” said lead author Michael Heneka, University of Bonn, in an interview with ARF.

In an earlier study, Heneka and colleagues showed that LC degeneration drives up amyloid deposition and glial inflammation, and intensifies memory deficits in APP23 transgenic mice (Heneka et al., 2006). The researchers treated the mice with DSP4, a LC-selective neurotoxin that reduced forebrain norepinephrine levels by about 70 percent. The treatment exacerbated brain Aβ deposition without changing the processing of amyloid precursor protein (APP), leading Heneka and colleagues to test whether Aβ degradation was playing a role. That’s what steered them toward microglia, which in their hands seemed to gobble up more Aβ when exposed to inflammatory stimuli such as lipopolysaccharide (LPS) or cytokines. “That was our first shot on goal,” Heneka said. “We found a huge effect.”

Given their previous work showing enhanced glial inflammation in DSP4-treated APP23 mice, the scientists wondered whether norepinephrine could have anti-inflammatory properties. They confirm their hunch in the present study, showing that addition of norepinephrine suppresses the upregulation of pro-inflammatory mediators (e.g., TNFα, iNOS, COX2) and chemokines (e.g., CCL2, CCL3, CCL5) normally seen in microglia exposed to fibrillar Aβ42. Furthermore, norepinephrine-treated microglia took up more Aβ, as revealed by immunohistochemistry, and migrated faster in a chemotaxis assay.

To look at microglial phagocytosis in vivo, Heneka’s team measured the extent to which Aβ deposits colocalized with the microglial activation marker CD11b in 12-month-old APPV717I mice depleted of brain norepinephrine by DSP4 treatment. Using confocal microscopy, the researchers found that DSP4-treated animals had 70 percent fewer Aβ-containing microglia. They did a similar confocal analysis using APP mice crossbred to mice with an EGFP knock-in mutation in the CX3CR1 locus, which makes microglia and other monocytes fluorescent. These studies also revealed lower amounts of Aβ within microglia of DSP4-treated mice. For further support, the researchers turned to an adoptive transfer experiment. They isolated fluorescent microglia from CX3CR1-EGFP transgenic mice, and injected them into the cortex of 16-month-old APPV717I recipient mice with or without prior DSP4 treatment to deplete norepinephrine levels. Dissecting the mouse brains 24 hours later, the researchers found that DSP4-treated animals had fewer Aβ-positive microglia and reduced migration distance among donor microglia. The researchers were able to reverse these effects by restoring norepinephrine to normal levels. They did this by giving the mice intraperitoneal injections of L-threo-DOPS, a norepinephrine precursor sold as an over-the-counter antidepressant in Japan and used to treat multiple system atrophy in the U.S. and Europe.

All told, the new data suggest that “early degeneration of LC neurons and their terminals, which will result first in a local but later in an overall norepinephrine deficiency, may facilitate the inflammatory reaction in response to Aβ deposition in the AD brain,” the authors write. In a recent paper, Piet Eikelenboom and colleagues at the University of Amsterdam, The Netherlands, propose a similar model whereby impaired control of microglial activation by cholinergic neurons triggers a pathogenic cascade leading to another mental disorder, delirium (Van Gool et al., 2010). The Dutch study and Heneka’s paper suggest that “a disturbance in neuron-microglia interactions, resulting in microglial activation by an escape from neuronal control” could contribute to a variety of neuropsychiatric disorders, Eikelenboom wrote in an e-mail to ARF (see full comment below).

Other studies have suggested that norepinephrine has benefits in a neurodegeneration context. Ahmad Salehi and colleagues at Stanford University in Palo Alto, California, showed that boosting norepinephrine improves contextual memory in a Down syndrome mouse model that overexpresses APP (Salehi et al., 2009 and ARF related news story). At the time of testing, these mice had reduced amounts of norepinephrine and LC degeneration. “We were thinking that more APP led to degeneration of LC,” Salehi told ARF. “Now this study says that if you bring down norepinephrine made by LC, that leads to less clearance of Aβ and more Aβ in the brain. There is some kind of vicious cycle here.”

While the current study shows that restoring norepinephrine levels in DSP4-treated mice lessens brain amyloid deposition, it does not address whether boosting norepinephrine can rescue behavioral deficits. These data appear in a soon-to-be-submitted paper, Heneka said. His team has created two new models for LC degeneration on an APP/PS1 background, and shown that L-threo-DOPS treatment improves hippocampal long-term potentiation and spatial memory, as assessed by the Morris water maze, in both strains.—Esther Landhuis


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Comments on News and Primary Papers

  1. It is frequently believed that in brain diseases characterized by a neuroinflammatory response, neurons are passive victims of glia activation by bystander lysis. However, recent findings show that reciprocial interactions between glia and neurons are essential for many critical functions in brain health and diseases. Microglial cells are actively involved in the control of neuronal activities and, at the same time, neurons influence glial functions through direct cell-cell contact and release of soluble mediators. These findings indicate that neurons are active players in the neuroinflammatory response.

    In an excellent review, Luise Minghetti and coworkers have discussed the evidence that, among neuronal signals that could have an active role in controlling glia activation, there are two major neurotransmitters: noradrenaline and acetylcholine (Carnevale et al., 2007).

    The present paper by Heneka and colleagues provides evidence for noradrenaline as a regulator of microglial functions facilitating Aβ clearance. In a recent paper, we discussed that impaired cholinergic control of microglia activation could be a crucial pathogenic mechanism for delirium (van Gool et al., 2010). Delirium is frequently seen in the elderly after systemic infections, especially in patients with pre-existent brain pathology, and is associated with high morbidity and mortality. [Editor’s note: Delirium has recently been linked to faster cognitive decline in Alzheimer’s; see ARF related news story.]

    The Heneka and van Gool papers suggest that a disturbance in the neuron-micoglia interactions, resulting in microglia activation by an escape from neuronal control, could be an important pathogenic mechanism in a broad variety of neuropsychatric disorders.

    With respect to the role of cholinergic and adrenergic systems in regulating microglia activation, it is most important that there exist available drugs to restore deficiencies in cholinergic and noradrenergic neurotransmission. Thus, we can test new ideas with already available drugs.

    View all comments by Piet Eikelenboom
  2. This report significantly extends the view that degeneration of noradrenergic (NA) neurons seen in Alzheimer disease (AD) actively participates in the disease progression. Previously, this group showed that toxin-induced lesion of NA neurons exacerbates AD-like neuropathological and behavioral features in mutant APP transgenic mice (1,2). While NA deficiencies can have multiple immediate effects on cellular function and blood flow, the current report provides evidence that NA in brain could regulate amyloid deposition by modulating the ability of microglia to clear Aβ via phagocytosis. In particular, the authors show that supplementing NA neuron-depleted mice with a norepinephrine (NE) precursor leads to enhanced migration of microglia and increased Aβ phagocytosis by microglia. Overall, the results suggest that NE replacement or NA receptors are valid therapeutic targets for disease modification in AD.

    It is uncertain whether NE replacement can actually attenuate AD-related neuropathology and/or behavioral impairments in vivo. While such results are likely to come in future work, other studies indicate that approaches targeting monoaminergic neurotransmission can have overt therapeutic effects in mouse models of AD. Specifically, chronic paroxetine (5-HT uptake inhibitor) treatment attenuates pathology in the 3xTg-AD model (3). This effect could be mediated by 5-HT-dependent modulation of BDNF expression (4). Both NA and 5-HT neurons degenerate very early in AD, and progressive degeneration of these neurons is recapitulated in a transgenic mouse model of AD (5), indicating that monoaminergic neurons are highly vulnerable to neurodegeneration from AD-related pathology.

    In turn, degeneration of monoaminergic neurons seems to promote AD-related pathology. Thus, NA and 5-HT neurotransmitter systems represent significant therapeutic targets for AD, and current mouse models (5) provide platforms for preclinical validation of such approaches. However, since AD-related degeneration of NA neurons occurs early in disease progression, and since current mouse models of AD seem to reflect early stages of AD pathogenesis, early detection of AD is required for such therapies to achieve clinical efficacy.

    View all comments by Michael K. Lee


News Citations

  1. Adrenaline Jolt—Potential Therapeutic Strategy for AD?

Paper Citations

  1. . Loss of pigmented dopamine-beta-hydroxylase positive cells from locus coeruleus in senile dementia of Alzheimer's type. Neurosci Lett. 1983 Aug 19;39(1):95-100. PubMed.
  2. . Neuronal degeneration in locus ceruleus and cortical correlates of Alzheimer disease. Alzheimer Dis Assoc Disord. 1987;1(4):256-62. PubMed.
  3. . Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer's disease. Neurobiol Aging. 2007 Mar;28(3):327-35. PubMed.
  4. . Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J Neurosci. 2006 Feb 1;26(5):1343-54. PubMed.
  5. . Systemic infection and delirium: when cytokines and acetylcholine collide. Lancet. 2010 Feb 27;375(9716):773-5. PubMed.

Other Citations

  1. APP23

External Citations

  1. Salehi et al., 2009

Further Reading


  1. . Systemic infection and delirium: when cytokines and acetylcholine collide. Lancet. 2010 Feb 27;375(9716):773-5. PubMed.
  2. . Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J Neurosci. 2006 Feb 1;26(5):1343-54. PubMed.
  3. . Microglia-neuron interaction in inflammatory and degenerative diseases: role of cholinergic and noradrenergic systems. CNS Neurol Disord Drug Targets. 2007 Dec;6(6):388-97. PubMed.

Primary Papers

  1. . Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine. Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):6058-63. PubMed.