. Reply to "Specificity of mechanisms for plaque removal after Abeta immunotherapy for Alzheimer disease". Nat Med. 2004 Feb;10(2):118-9. PubMed.

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  1. Akiyama and McGeer describe focal clearance of senile plaques in the cortex of a patient with Alzheimer’s disease in an advanced stage. They interpret this as a result of “microglia and macrophage invasion of the affected area.” Their data are remarkable for showing localized areas of clearing related to a hemorrhagic ischemic infarction, which necessarily implies disrupted blood-brain barrier. Although their Fig. 1C shows intensely concentrated typical microglia, an inset in the top part of Fig. 1C shows large cells resembling macrophages. We previously described in Alzheimer’s disease brains large macrophages infiltrating and partially clearing senile plaques (Fiala et al., 2002). One answer to Akiyama's and McGeer's findings is that disrupted blood-brain barrier allowed immigration of blood-borne macrophages and phagocytosis of Aβ by macrophages. Our Fig. 6 shows that infiltrating macrophages can phagocytose and partially clear senile plaques.

    Why are brain phagocytic cells of Alzheimer’s disease patients not able to clear amyloid-β deposits? In their reply to Akiyama and McGeer, Nicoll et al. point out that the vaccinated patient in the Elan trial had an inflammatory response by both microglia and T cells; whereas only microglia could clean extensive areas of amyloid-β, T cells could induce pathological inflammation. The interpretation of vaccine efficacy centers on Aβ antibodies entering the brain and opsonizing Aβ for microglial phagocytosis (Hock et al., 2003). The present evidence has been epidemiological rather than a direct demonstration of antibody opsonization of microglia in vaccinated brain.

    Akiyama and McGeer stress the differences between the mouse and human immune system. The inflammatory response to Aβ in transgenic mice is much lower than in Alzheimer’s disease patients due to poor recognition of human Aβ by mouse C1q. The progression of Alzheimer’s disease research from transgenic animals to patients might be slow and difficult. We are seeking answers to specific defects of Alzheimer’s patients by studying immune responses in peripheral blood of human patients.

    References:

    . Cyclooxygenase-2-positive macrophages infiltrate the Alzheimer's disease brain and damage the blood-brain barrier. Eur J Clin Invest. 2002 May;32(5):360-71. PubMed.

    . Continuous interleukin-6 application in vivo via macroencapsulation of interleukin-6-expressing COS-7 cells induces massive gliosis. Glia. 2001 Sep;35(3):234-45. PubMed.

    View all comments by Milan Fiala
  2. There has been considerable interest in using immunization strategies for clearing pre-existing Aβ. Studies in AD-models showed that active or systemic passive immunizations with Aβ peptide reduced cerebral plaques and improved behavior. However, clinical translation of active immunization failed miserably due to inflammation and hemorrhage produced in patients that received Aβ-vaccine (Nicoll et al., 2002). Follow-up studies confirmed that weekly intraperitoneal injections of anti-Aβ for five months resulted in microhemorrhage in APP23 mice with cerebral amyloid angiopathy (CAA) (Pfeifer et al., 2002), and that immunization of C57 mice with Aβ-42 and pertussin toxin developed inflammation in brain and spinal cord (Furlan et al., 2003). I have put forward the idea of immuno-neutralization and intracerebroventricular passive immunization in Tg2576 back in late 90s. Our laboratory has established an effective method of intracerebroventricular (icv) passive immunization that circumvented problems associated with active and systemic passive immunization (Chauhan and Siegel, 2002, 2003). We showed that a single icv injection of anti-Aβ antibody neutralized preexisting Aβ and restored Aβ-induced synaptotoxicity and glial reaction (Chauhan and Siegel, 2002), without producing inflammation or hemorrhage (Chauhan and Siegel, 2003) up to 4 weeks post-treatment in a Swedish mutant model of AD (Tg2576). Furthermore, we demonstrated that a single icv injection of anti-Aβ maintained a reduction of cerebral A by ~50 percent for up to 4 weeks and reduced cerebral inflammation by ~40 percent for up to one week in two-month-old (no plaques, no CAA), and in eight-month-old (abundant plaques and CAA) stages without producing microhemorrhage in an AD-model harboring Swedish plus Indiana mutations (TgCRND8) (unpublished data). It is interesting to note that our work has not received expected level of attention in spite of being intriguing and outstanding in the field of immunotherapy in AD.

    See also:

    Chauhan NB, Lichtor T, Siegel GJ. To be presented at the 9th International Meeting of Alzheimer's Association, 2004.

    References:

    . Distribution of intraventricularly administered antiamyloid-beta peptide (Abeta) antibody in the mouse brain. J Neurosci Res. 2001 Oct 15;66(2):231-5. PubMed.

    . Reversal of amyloid beta toxicity in Alzheimer's disease model Tg2576 by intraventricular antiamyloid beta antibody. J Neurosci Res. 2002 Jul 1;69(1):10-23. PubMed.

    . Intracerebroventricular passive immunization with anti-Abeta antibody in Tg2576. J Neurosci Res. 2003 Oct 1;74(1):142-7. PubMed.

    View all comments by Neelima Chauhan
  3. Recently, a highly publicized clinical trial of patients vaccinated with the amyloid-β (Aβ) protein was terminated when several patients receiving the vaccine displayed CNS complications that included extensive encephalitis and macrophage infiltration into the brain parenchyma; they also had a reduction in amyloid plaques. In this report, Akiyama and McGeer report a reduction in senile plaques in a region of the cortex of a 79-year-old Alzheimer’s patient showing incomplete ischemia. They suggest that the observed plaque reduction is due to the activity of microglia and macrophages, which immigrated into the affected region, and further propose that encephalitis, regardless of cause, may promote the removal of amyloid plaques through enhanced phagocytosis.

    The idea that local ischemia and the resulting inflammatory response may create conditions that favor removal of existing plaques through the action of local phagocytic cells is provocative. Since this work deals with a single case, the results of further confirmatory work will be eagerly awaited to see if this phenomenon is generally true. The level of inflammation seen in most late-stage AD patients is quite high and often autotoxic. However, in the case presented here, it is important to point out that the level of ischemia was insufficient to cause significant neuronal cell death, thus leaving the neuropil essentially intact. How amyloid plaques formerly residing in this region (which we assumed to be the dense-core, classical types and not the diffuse types, although this also remains to be determined) were removed is not known, but there are a few interesting possibilities that need to be further investigated. For example, the authors suggest that the disappearance of plaques may be related to the turnover rate of Aβ deposits. Although the lifespan of amyloid plaques and the turnover rate of Aβ in the brain parenchyma of AD patients are also unknown, an ischemia-related reduction in Aβ production and/or accumulation with no change in Aβ clearance could potentially explain this observation. Alternatively, if the source of Aβ is the local vasculature, the depletion or elimination of blood flow in the ischemic zone would be expected to cut the supply line of Aβ, while possibly having less effect on Aβ clearance. The abundant presence of reactive microglia in the ischemic zone favors the idea that most or the entire Aβ within this zone, and especially that contained within plaques, was removed by the phagocytic activity of microglia and macrophages. (As a personal note, we would like to understand what remains in these areas of "removed" plaques; for example, are glial scars—i.e., GFAP-wraps—still present? Do these areas contain traces of cellular debris? Do they show a loss of neuronal processes?)

    These observations suggest that controlling the level of response of local phagocytic cells to the point where the neuropil is preserved and the local Aβ load is removed may have beneficial effects for AD patients. Such an approach may prove to be difficult in practice since the severity of pathology (and thus the local level of inflammation) can vary dramatically from one brain region to the next in any given patient. It will be of great interest to see if all encephalitic reactions are accompanied by significant local plaque clearance.

    View all comments by Robert Nagele

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