There was little doubt that activated microglia were part of an acute cellular response to an injurious stimulus, which for Oehmichen and Huber consisted of implanting glass cover slips into the rabbit brain.
A more sophisticated paradigm of eliciting microglial activation whose origins date back to the work of Nissl at the turn of the 20th century, and advocated by Kreutzberg and colleagues beginning in the 1960s was the facial nerve axotomy paradigm.
The neurofibrillary degeneration that occurs in Alzheimer’s disease (AD) is thought to be the result of a chronic and damaging neuroinflammatory response mediated by neurotoxic substances produced by activated microglial cells. Molecular consequences of activated microglia in the brain: overactivation induces apoptosis.
Any extrapolations made from such in vitro data are therefore unlikely to apply to most in vivo scenarios of microglial activation with the possible exception of a bacterial CNS infection.
Case in point, ameboid microglia in vivo do not produce IL-1 (Hurley et al., 1999 ), as suggested by in vitro studies (Giulian et al., 1986 ).
Thus, with regard to the question posed in this special issue: where did we get lost, the short answer is, we got lost early on by misinterpreting biological functions of microglia.
The purpose of this paper is to describe how this misconception came about and how it became entangled with the concept of detrimental neuroinflammation which is now believed by many to underlie not only Alzheimer’s disease (AD) pathogenesis but a number of other major neurodegenerative conditions, including Parkinson’s disease, amyotrophic lateral sclerosis and HIV-associated dementia.
We have previously discussed this discrepancy between in vivo and in vitro concepts of microglial activation (Streit et al., 1999 ), pointing out that the generation of microglial cell cultures involves extreme brain damage (chopping and trituration of dissected tissues) inevitably causing immediate activation of microglia and their transformation into brain macrophages. Microglia are the major cell type expressing MHC class II in human white matter.
When these activated microglia-derived brain macrophages are additionally stimulated with LPS, the result is superactivated cells that produce not only copious quantities of IL-1 but many other secretory products. (1988) just a couple of years later by showing that IL-1 m RNA synthesis was induced in these cultured cells following their stimulation with bacterial lipopolysaccharide (LPS). With this introduction to neurobiology of LPS-mediated macrophage activation, already well-established and accepted in immunology circles, the flood gates were opened for studying microglial activation in vitro. Pubmed Abstract | Pubmed Full Text | Cross Ref Full Text Hetier, E., Ayala, J., Denefle, P., Bousseau, A., Rouget, P., Mallat, M., and Prochiantz, A. Brain macrophages synthesize interleukin-1 and interleukin-1 m RNAs in vitro. In this paper, I make the point that AD is not an inflammatory condition, and reconstruct the sequence of events during the 1980s and 1990s that I believe led to the development of this faulty theory. One might reasonably argue that a microglial renaissance occurred during the mid-to late 1980s. Pubmed Abstract | Pubmed Full Text | Cross Ref Full Text Liu, B., Wang, K., Gao, H. Although anatomists of the early 20th century, such as Nissl and del Rio Hortega, had already made seminal contributions toward understanding microglial biology, for reasons unknown microglia remained largely hidden away from mainstream neuroscience for much of the decades following these early studies. Microglia activation in sepsis: a case–control study.