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...  Read more

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.

References:
Carnevale D, De Simone R, Minghetti L (2007). Microglia-neuron interaction in inflammatory and degenerative diseases:role of cholinergic and noradrenergic systems. CNS Neurol Disord Drug Targets 6: 388-397. 73858

van Gool WA, van de Beek, D, Eikelenboom P (2010) Systemic infections and delirium: when cytokines and acetylchoine collide. Lancet 375: 773-775. 100533

View all comments by Piet Eikelenboom

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...  Read more

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.

References:
1. Heneka, M.T., M. Ramanathan, A.H. Jacobs, L. Dumitrescu-Ozimek, A. Bilkei-Gorzo, T. Debeir, M. Sastre, N. Galldiks, A. Zimmer, M. Hoehn, W.D. Heiss, T. Klockgether, and M. Staufenbiel. 2006. Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J Neurosci 26:1343-1354. Abstract

2. Kalinin, S., V. Gavrilyuk, P.E. Polak, R. Vasser, J. Zhao, M.T. Heneka, and D.L. Feinstein. 2007. Noradrenaline deficiency in brain increases beta-amyloid plaque burden in an animal model of Alzheimer's disease. Neurobiol Aging 28:1206-1214. Abstract

3. Nelson, R.L., Z. Guo, V.M. Halagappa, M. Pearson, A.J. Gray, Y. Matsuoka, M. Brown, B. Martin, T. Iyun, S. Maudsley, R.F. Clark, and M.P. Mattson. 2007. Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice. Exp Neurol 205:166-176. Abstract

4. Mattson, M.P., S. Maudsley, and B. Martin. 2004. BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci 27:589-594. Abstract

5. Liu, Y., M.J. Yoo, A. Savonenko, W. Stirling, D.L. Price, D.R. Borchelt, L. Mamounas, W.E. Lyons, M.E. Blue, and M.K. Lee. 2008. Amyloid pathology is associated with progressive monoaminergic neurodegeneration in a transgenic mouse model of Alzheimer's disease. J Neurosci 28:13805-13814. Abstract

View all comments by Michael K. Lee