Two recent studies confirm that local inflammation inhibits adult neurogenesis in the hippocampus and, in a promising advance, they find evidence that systemic administration of common nonsteroidal antiinflammatory drugs (NSAIDs) can restore some of the neurogenesis. These findings, from groups working in different disease models, add another angle to the rationale behind the therapeutic use of NSAIDs to protect the brain in Alzheimer's disease and in normal aging.

Already a decade ago, in-vitro data suggested that inflammatory molecules, such as the cytokines released by activated microglia, could regulate the differentiation of dentate gyrus stem cells into neurons and glia (Mehler et al., 1993). In subsequent years, researchers began to link perturbations in hippocampal neurogenesis to cognitive defects in AD and aging, as well as stroke and epilepsy. And in a separate line of research, Theo Palmer, Michelle Monje, and colleagues at Stanford University in California demonstrated last year that the cognitive damage associated with some cancer radiation therapy can be partly blamed on the inhibition of hippocampal neurogenesis (Monje et al., 2002). Monje et al. showed that, rather than damaging the precursors or differentiated neurons directly, radiation therapy disastrously perturbs the “microenvironment” of the stem cells and increases the number of activated microglia.

In the November 11 PNAS, Olle Lindvall, Christine Ekdahl, and their colleagues at Lund University in Sweden implicate inflammation as one of those microenvironment changes. These researchers have been modeling the reduction of hippocampal neurogenesis—which is accompanied by inflammation—in epilepsy. In their recent study, Lindvall and colleagues found that inflammation, whether triggered by status epilepticus or by bacterial lipopolysaccharide (LPS), directly impaired hippocampal neurogenesis in rats. The decreased neurogenesis was accompanied and probably fueled by the activation of microglia, as neurogenesis was tightly correlated with the degree of microglial activation. Minocycline, an NSAID (and an antibiotic) that specifically inhibits microglial activation, was able to significantly boost neurogenesis in spite of status epilepticus- or LPS-induced inflammation (see ARF related news story, Hirsch et al., 2003, Kriz et al., 2002).

Similar findings were reported in the December 5 Science by Monje and colleagues, who found that inflammation associated with both cranial irradiation and LPS treatment substantially reduced hippocampal neurogenesis in vivo. NSAID indomethacin reversed this reduction. The researchers also looked more closely at the possible role of microglia in creating a microenvironment disruptive to neurogenesis. They found that the proinflammatory cytokines interleukin-6 (IL-6) or tumor necrosis factor-α (TNFα) alone, but not IL-1β or interferon-γ, lowered neurogenesis (but not gliogenesis) in vitro by about half. In the presence of conditioned media from astroglia, inhibition of IL-6 alone was sufficient to restore the neurogenesis, suggesting a central role for this cytokine (see also Licastro et al., 2003, Vallieres et al., 2002).

In their editorial accompanying the recent Monje et al. article, Gerd Kempermann of the Max Delbrük Center for Molecular Medicine in Berlin, Germany, and Harald Neumann of the European Neuroscience Institute in Göttingen, Germany, note that "inhibition of neurogenesis by IL-6 might be due to increased production of astrocytes (or perhaps other glial cells) at the expense of neuronal progenitor cells, particularly as astrocytes and neuronal precursor cells seem to share a common stem cell. Alternatively, inhibition of neurogenesis by IL-6 may be a consequence of a decrease in neuronal progenitor cell proliferation or an increase in the number of these cells undergoing apoptosis."

Apropos the question of what indomethacin might be doing to protect neurogenesis, Monje et al. point out that NSAIDs may have effects on the stem cell microenvironment beyond blocking microglial release of IL-6. For example, the drugs have effects via the hypothalamic-pituitary-adrenal axis and may change vascular permeability and reduce the recruitment of proinflammatory endothelial cells.—Hakon Heimer.

Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13632-7. Epub 2003 Oct 27. Abstract

Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science. 2003 Dec 5;302(5651):1760-5. Epub 2003 Nov 13. Abstract

Kempermann G, Neumann H. Microglia: the enemy within? Science. 2003 Dec 5;302(5651):1689-90. Abstract


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  1. These two recent exciting studies demonstrate that local inflammation inhibits adult neurogenesis in the hippocampus in different diseased animal models [1,2]. The suppression of hippocampal neurogenesis by activated microglia may explain the cognitive dysfunction and adds another angle to the rationale behind immunotherapeutics in Alzheimer's disease. The authors showed that decreased neurogenesis was accompanied with, and probably fueled by, activation of microglia, as neurogenesis was tightly correlated to the degree of microglial activation. Further support comes from the use of nonsteroidal antiinflammatory drugs, like indomethacin, and a selective inhibitor of microglia activation, minocycline, which were able to restore hippocampal neurogenesis in inflammation without affecting neurogenesis in control animals [1].

    Inflammatory changes—including microgliosis, astrocytosis, complement activation, cytokine elevation, and acute phase protein changes—are thought to represent, at least in part, a response to the early accumulation of Aβ1-42 in the AD brain [3-6]. It appears that Aβ or its fibrillated form is recognized in the CNS as a molecule that needs to be cleared and provokes activation of microglia and astrocytes.

    Immunotherapy aimed at Aβ vaccination in AD transgenic mice raised unprecedented hopes for an effective treatment of AD. On the efficacy side, there is clear evidence that Aβ immunization in mice induces a clearance of Aβ plaques and improves associated cognitive disturbances [7-13]. It appears that the induction of antibodies to Aβ plays the primary role in the vaccine-mediated clearance of Aβ from the brain, as passive transfer of Aβ antibodies has shown similar beneficial neuropathological effects [13].

    The recent clinical trials of AD immunotherapy failed because of unexpected neuroinflammation, and a major concern may be attributed to potential proinflammatory consequences following Aβ immunization, which may lead to overactivation of microglia, even leading to acceleration of neurodegeneration.

    Brain inflammation causes inhibition of neurogenesis both in the basal continuous formation of new neurons in the intact hippocampal formation and in the increased neurogenesis in response to a brain insult. The impairment of neurogenesis depends on the degree of microglia activation, irrespective of whether there is damage or not in the surrounding tissue. While neurogenesis appears to be increased in the brains of patients with AD, progressive cell loss is still observed [14,15]. This may be due to the disruptive micro environment to neurogenesis in the AD brain which may be toxic to new neurons [15].

    The beneficial effect of immunotherapy on Aβ clearance could be exploited, avoiding inflammation by controlling microglial activation and supporting neurogenesis. This could be prominent amongst those factors that determine whether immune therapy will be successful as a treatment for AD patients [16].

    Plaque clearance as a result of immunotherapy may depend on multiple mechanisms, one involving direct interaction of antibodies, or F(ab')2 fragments, with the deposits resulting in disaggregation, and another involving cell-mediated clearance, possibly involving Fc receptor activation. The two mechanisms may occur independently, or may operate in tandem, with cellular removal of amyloid-β after disaggregation [17].

    However, Fc regions of antibody-antigen complexes, amplified by cellular mediators and activated complement, via Fc receptors (FcR), may initiate the inflammatory response [18].

    No data are available so far on the quantitative decrease of Aβ concentration necessary to reduce Aβ deposition and the amount of antibodies required for efficient immunotherapy which might at the same time avoid additional inflammation.

    Modulation of the FcR pathway may be an efficient practical therapeutic approach for controlling autoantibody-mediated inflammation induced by self-antigens or antibodies in immunotherapeutic strategies for treatment of AD. One of these is the administration of intravenous immunoglobulin (IVIg), which has well-recognized antiinflammatory activities independent of the antigen-specific effect [19].

    Another approach may be passive immunization with antibodies devoid of Fc, which may prevent overactivation of microglia and, thus, attenuation of autoantibody-triggered neuroinflammation. The ability of single-chain antibody 508F(Fv) to dissolve already formed Aβ fibrils suggests that only the antigen-binding site of the antibodies (Fab) was involved in modulation of β amyloid conformation and not the Fc region [20]. Studies with F(ab')2 fragments of anti-Aβ antibodies using in-vivo topical application demonstrated that the mechanism does not require Fc receptor-mediated cellular activation in plaque clearance by immunotherapy [21].

    To definitively ascertain the role of microglial FcR in Aβ immunotherapies, APP Tg2576 mice bred into FcR-/- mice were used [22]. Data show that microglia isolated from FcR γ-/- mice exhibit almost no uptake of anti-Aβ immune complexes via FcR. Aggregated Aβ was readily scavenged by both FcR-γ+/+ and FcR-γ-/- microglia in the absence of anti-Aβ. Thus, there did not appear to be any defects in the non-FcR-mediated Aβ uptake by microglia in the FcR-γ-/- mice [22].

    Fc receptors also interact bidirectionally with complement receptor proteins [23-27]. Complement activation in AD brain has been proposed to be especially crucial to the phenomenon of "bystander lysis," in which healthy neuronal tissue adjacent to plaques is thought to undergo nonspecific injury and degeneration [28,29].

    Proinflammatory cytokines may be involved in the interaction of Fc receptors and complement biosynthesis, as IL-6, shown to modulate production of both C3 and C9 complement proteins following immune stimulation [18,23-25]. C9 is an integral member of membrane attack complex, which is the mechanism for complement-mediated cell lysis, raising the possibility that activation of Fc receptors may very well clear Aβ, but might drastically increase local inflammation and neuronal injury in the vicinity of Aβ plaques in the process [3]. Furthermore, in a recent paper, Kemermann and Neumann [26] claim that IL-6 is interfering with the production of new neurons, since it diverts neuronal progenitor cells to become astrocytes rather than neurons.

    It is believed that the discovery that the diseased adult human brain is capable of neurogenesis in response to neuronal loss will be of major relevance for development of therapeutic approaches in the treatment of neurodegenerative diseases.

    It is tempting to believe that the beneficial effect of the immunotherapy might stem less from alleviation of the toxic agent and more so from promotion and/or restoration of neurogenesis, all resulting in a normal number of functioning neurons.


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News Citations

  1. Building Blocks for Neurodegenerative Disease Therapy

Paper Citations

  1. . Cytokine regulation of neuronal differentiation of hippocampal progenitor cells. Nature. 1993 Mar 4;362(6415):62-5. PubMed.
  2. . Irradiation induces neural precursor-cell dysfunction. Nat Med. 2002 Sep;8(9):955-62. PubMed.
  3. . The role of glial reaction and inflammation in Parkinson's disease. Ann N Y Acad Sci. 2003 Jun;991:214-28. PubMed.
  4. . Minocycline slows disease progression in a mouse model of amyotrophic lateral sclerosis. Neurobiol Dis. 2002 Aug;10(3):268-78. PubMed.
  5. . Interleukin-6 gene alleles affect the risk of Alzheimer's disease and levels of the cytokine in blood and brain. Neurobiol Aging. 2003 Nov;24(7):921-6. PubMed.
  6. . Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J Neurosci. 2002 Jan 15;22(2):486-92. PubMed.
  7. . Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13632-7. PubMed.
  8. . Inflammatory blockade restores adult hippocampal neurogenesis. Science. 2003 Dec 5;302(5651):1760-5. PubMed.
  9. . Neuroscience. Microglia: the enemy within?. Science. 2003 Dec 5;302(5651):1689-90. PubMed.

Further Reading


  1. . Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13632-7. PubMed.
  2. . Inflammatory blockade restores adult hippocampal neurogenesis. Science. 2003 Dec 5;302(5651):1760-5. PubMed.
  3. . Neuroscience. Microglia: the enemy within?. Science. 2003 Dec 5;302(5651):1689-90. PubMed.

Primary Papers

  1. . Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13632-7. PubMed.
  2. . Inflammatory blockade restores adult hippocampal neurogenesis. Science. 2003 Dec 5;302(5651):1760-5. PubMed.
  3. . Neuroscience. Microglia: the enemy within?. Science. 2003 Dec 5;302(5651):1689-90. PubMed.