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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