Butovsky O, Koronyo-Hamaoui M, Kunis G, Ophir E, Landa G, Cohen H, Schwartz M. Glatiramer acetate fights against Alzheimer's disease by inducing dendritic-like microglia expressing insulin-like growth factor 1. Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11784-9. PubMed.
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Butovsky and colleagues have reported that “Glatiramer acetate fights against Alzheimer’s disease by inducing dendritic-like microglia expressing insulin-like growth factor 1.” The authors have not shown that glatiramer fights against AD, per se. They do not know whether it will help, harm or be without benefit, because they have not administered it to AD patients. What the authors have done is to administer 5 subcutaneous doses of glatiramer to doubly transgenic APP/PS1 mice and have shown, compared with untreated littermates, less amyloid deposition and less impairment in water maze testing. Their results are comparable to the earlier findings of Frenkel et al. (2006), who administered glatiramer intranasally rather than subcutaneously to transgenic mice. Glatiramer is a mixture of synthetic polypeptides which is currently in use to treat multiple sclerosis. Its mechanism of action is still unclear.
The theory of Butovsky et al. is that the vaccination caused a phenotypic shift in microglial expression from production of the complement receptor CD11b to CD11b/CD11c, resulting in improved phagocytosis and increased neurogenesis in the transgenic mice. What needs to be emphasized is that transgenic mouse models of AD are not AD itself, and to assume that they are, especially with respect to engaging the adaptive immune system through vaccination, can have severe consequences. This was the case with Elan’s clinical trial for an Aβ vaccine where immune stimulation induced sterile meningitis and cerebral damage in about 5 percent of the cases despite spectacular results in transgenic mice.
There are notable differences in the pathology of AD and transgenic mouse models. For example, in AD there is further processing of the Aβ deposits, converting them into a more insoluble state. In humans there is a higher level of inflammation, caused in large part by vigorous activation of the human complement system by Aβ deposits. Since mouse C1q poorly recognizes human Aβ deposits, complement activation in transgenic mice is minimal. In human AD, there is full activation of the complement system resulting in neuronal destruction by the membrane attack complex. The latter may be the most problematical consequence of immune stimulation in AD.
Butovsky et al. concluded that anti-inflammatory therapy should not be used in AD, and that appropriate immune stimulation should be an effective treatment. If this theory were correct, then individuals taking anti-inflammatory therapy should have a higher risk of developing AD. The opposite is the case. We reviewed 17 epidemiological studies from nine different countries in 1996 (McGeer et al., 1996). All but two showed decreased odds of contracting AD amongst those suffering from arthritis or known to be taking anti-inflammatory drugs. We updated the review in 2006 (McGeer and McGeer, 2006), specifically concentrating on NSAIDs since these are the most widely used anti-inflammatory agents. Twelve of 14 studies showed a decreased risk of developing AD. In addition, eight of eight transgenic animal studies showed a reduction in both Aβ deposits and behavioral deterioration in mice given traditional NSAIDs.
Butovsky et al. noted that their theory “is in line with studies showing that anti-inflammatory drugs, such as cyclooxygenase 2 inhibitors, do not benefit AD.” This is certainly true, since four clinical trials of selective COX-2 inhibitors have failed. But COX-2 is a questionable target for the brain. It is one of the few organs of the body which constitutively expresses this enzyme, which is most highly concentrated in pyramidal neurons. Presumably, there is a significant physiological function associated with this high level of expression, and blocking prostaglandin production in pyramidal neurons could have negative consequences. Moreover, COX-2 inhibitors have been too recently introduced for any epidemiological evidence to have accumulated showing whether their long-term use increases or reduces the risk of developing AD. However, COX-2 inhibitors have been tried without benefit in transgenic animal studies (see Kukar et al., 2005).
It is not beyond the realm of possibility that ways can be found in humans of stimulating microglia to phagocytose while blunting the self-destruction they cause by excessive output of oxygen free radicals, prostaglandins, inflammatory cytokines, proteases, complement proteins, and other toxic materials. But whether or how this might be done is still unknown. Butovsky et al. have suggested a possibility which certainly deserves further exploration. We can hope they have set investigators on a promising trail, but direct application of their theory to AD cases should be approached with caution.
References:
McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurology. 1996 Aug;47(2):425-32. PubMed.
McGeer PL, McGeer EG. NSAIDs and Alzheimer disease: epidemiological, animal model and clinical studies. Neurobiol Aging. 2007 May;28(5):639-47. Epub 2006 May 11 PubMed.
Kukar T, Murphy MP, Eriksen JL, Sagi SA, Weggen S, Smith TE, Ladd T, Khan MA, Kache R, Beard J, Dodson M, Merit S, Ozols VV, Anastasiadis PZ, Das P, Fauq A, Koo EH, Golde TE. Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Abeta42 production. Nat Med. 2005 May;11(5):545-50. PubMed.
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