CommentaryInflammation and Alzheimer’s disease
Introduction
A virtual textbook of inflammatory mediators has been observed in the Alzheimer’s disease (AD) brain over the last 15 years. These mediators are typically at undetectable or background levels in samples from nondemented elderly (ND) patients, and have been investigated at immunohistochemical, biochemical, and molecular levels. As with all new developments in science, perception of these findings has evolved over time. Initially, resistance was high. Many of the early results were dismissed as artifact, an impossibility given the “immunologic privilege” of the brain. This narrow view, however, gradually eroded thanks to seminal work in classical neuroimmunology [cf. 209,210,591,592] as well as a burgeoning literature confirming and extending the presence of inflammatory molecules in AD brain [for previous reviews, see 6,350,384,453,457]. It is now clear that the brain may have many unique immunologic properties, but it is by no means an immunologically isolated organ.
With this understanding, new challenges have arisen. Are inflammatory mechanisms actually causing damage in AD or are they present merely to remove the detritus from other, more primary pathologic processes? Are anti-inflammatory drugs a viable therapeutic option for AD? Such questions, too, are beginning to find answers. Direct and tangential evidence of a neurodegenerative role for AD inflammatory processes has been provided from basic research studies, and clinical research, although still inconclusive with respect to the best choice of an anti-inflammatory therapeutic, has widely suggested that conventional nonsteroidal anti-inflammatory drugs (NSAIDs) may delay the onset and slow the progression of AD [reviewed in 351].
Many misunderstandings and gaps in our knowledge about AD inflammation nonetheless persist. The fact that AD inflammation appears to arise from within the CNS, with little or no involvement of lymphocytes or monocytes beyond their normal surveillance of brain [591], has put it out of the realm of conventional neuroimmunologic studies that focus largely on humoral aspects of such CNS inflammatory disorders as multiple sclerosis. How and when inflammation arises in the course of AD has not yet been fully resolved, and for some the pathophysiologic significance of AD inflammation itself still remains an issue. Perhaps most of all, AD inflammation research has most often been compartmentalized, with some groups specializing in cytokines, others in complement, chemokines, growth factors, oxidative stress, microglial activation, astrocyte reactivity, or other areas. In fact, however, inflammatory mechanisms are highly interactive and almost never occur in isolation from each other.
For these reasons, a review that goes beyond the simple tabulation of AD inflammatory mediators may be timely. Here, we have attempted to martial the evidence for a pathophysiologically relevant role of AD inflammation and to take into account the myriad interactions of inflammatory mediators. By doing so, it may be possible to gain new insights into how inflammation fits into the overall framework of AD pathology as well as how best to design new therapeutics to combat AD inflammation.
Section snippets
Inflammatory pathways in the AD brain
From immunohistochemical, biochemical, and molecular studies of AD and ND postmortem tissue, and, in particular, by reference to known inflammatory pathways in the periphery, it has become tenable to attempt to organize the many inflammatory mediators uncovered in the AD brain into a working model (see enclosed poster). At its center are amyloid β peptide (Aβ), neurofibrillary tangles, and neuronal degeneration, the hallmarks of AD for nearly a century. Just as damaged tissue and the chronic
Microglia
Activated microglia cluster at sites of aggregated Aβ deposition and deeply interdigitate neuritic plaques. Because they are related to peripheral macrophages [97], [302], they are one of the most obvious targets for research in AD inflammation and, indeed, much of the early impetus for research into inflammatory processes in AD came from the discovery that, like activated peripheral macrophages, many of the microglia in pathologically vulnerable areas of the AD brain express major
Animal models of AD neuroinflammation
A novel animal model has been reported that uses chronic, low-dose infusion of the inflammogen LPS into the ventricular system. Several parallels with AD inflammation are observed in this model, including increased activation of microglia, astrogliosis, increased tissue levels of IL-1β and TNF-α, elevated APP induction, temporal lobe pathology associated with cell loss and microglial reactivity [195], [594], and a working memory deficit [195], [197], [198]. Magnetic resonance imaging studies
Inflammation as a cause of damage to the AD brain
Inflammation, whether in the brain or the periphery, is almost always a secondary response to some more primary pathogen. This does not mean, however, that it is unimportant. In head trauma, for example, the blow to the head is the primary event. What will typically concern the neurologist and neurosurgeon more, however, is the secondary inflammatory response that will ensue and likely cause more neuron loss than the initial injury. Thus, a secondary inflammatory response often comes to be as
Anti-inflammatory drug studies
As the previous sections establish, chronic, local inflammatory responses occur in pathologically vulnerable areas of the AD brain. These responses orchestrate numerous well-known phenomena in AD pathology such as microglial clustering at sites of Aβ deposition and exacerbate the damage done by other AD pathogenic factors. It follows, then, that anti-inflammatory therapy should be beneficial in delaying the onset or slowing the progression of AD. This hypothesis has been directly and indirectly
Future directions
One of the issues that has not achieved complete consensus among the multiple authors of this review concerns cytoprotective versus cytopathic actions of several inflammatory mediators, particularly TNF-α and the complement anaphylatoxins. On the one hand, the very name for TNF-α, tumor necrosis factor-α, much less its potent effects on angiogenesis and its potent ability to activate other destructive inflammatory mechanisms, makes it implausible that this cytokine would not, overall, exert
Conclusion
It is indisputable that neuroinflammation occurs in the AD cortex. Mechanisms that parallel those encountered in localized peripheral inflammatory responses are readily identified, along with detailed pathways for how the mechanisms interact. There are also obvious parallels in the AD brain to the conditions that stimulate localized peripheral inflammation: the chronic presence of highly insoluble deposits of abnormal proteins, as well as chronic damage to tissue. What is, in fact, surprising
Acknowledgements
We are grateful to Parke–Davis Pharmaceuticals for their continuing support of the Neuroinflammation Working Group and the development of this manuscript.[3], [6], [100], [130], [162], [199], [204], [209], [210], [223], [304], [333], [360], [381], [383], [385], [403], [453], [457], [513], [517], [562], [592], [606], [612]
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