Vascular consequences of passive Aβ immunization for Alzheimer's disease. Is avoidance of "malactivation" of microglia enough?

Steven W Barger

doi:10.1186/1742-2094-2-2

Steven W Barger

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https://doi.org/10.1186/1742-2094-2-2

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The role of inflammation in Alzheimer's disease (AD) has been controversial since its first consideration. As with most instances of neuroinflammation, the possibility must be considered that activation of glia and cytokine networks in AD arises merely as a reaction to neurodegeneration. Active, healthy neurons produce signals that suppress inflammatory events, and dying neurons activate phagocytic responses in microglia at the very least. But simultaneous with the arrival of a more complex view of microglia, evidence that inflammation plays a causal or exacerbating role in AD etiology has been boosted by genetic, physiological, and epidemiological studies. In the end, it may be that the semantics of "inflammation" and glial "activation" must be regarded as too simplistic for the advancement of our understanding in this regard. It is clear that elaboration of the entire repertoire of activated microglia – a phenomenon that may be termed "malactivation" – must be prevented for healthy brain structure and function. Nevertheless, recent studies have suggested that phagocytosis of Aβ by microglia plays an important role in clearance of amyloid plaques, a process boosted by immunization paradigms. To the extent that this clearance might produce clinical improvements (still an open question), this relationship thus obligates a more nuanced consideration of the factors that indicate and control the various activities of microglia and other components of neuroinflammation.

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Alzheimer's disease (AD) is a progressive degeneration of neural structure and function that arises in the cerebral cortex
While some have argued that cerebral amyloid angiopathy (CAA) is of little consequence in AD [28], the elaboration of the deposition that appears to occur under conditions of "beneficial inflammation" is on par with that seen in hereditary cerebral hemorrhage with angiopathy-Dutch type and is certainly a risk factor for devastating levels of hemorrhage
While many had argued that microglial "activation" by amyloid βpeptide (Aβ) was at least partially responsible for AD-associated degeneration, others had pointed to microglial phagocytosis as a desirable consequence of activation

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Introduction

Alzheimer's disease (AD) is a progressive degeneration of neural structure and function that arises in the cerebral cortex. Journal of Neuroinflammation 2005, 2:2 http://www.jneuroinflammation.com/content/2/1/2 glia as a sign of "neuroinflammation," it can be said that inflammatory responses have been evident in AD for at least 40 years [1] It was not until the late 1980s that investigators were willing to express the hypothesis that inflammatory events were causal or otherwise contributing to the progression of the disease. Microglia elevate their expression of neurotrophic factors under many of the same conditions in which they show inflammationrelated responses such as phagocytosis, retraction of processes, release of excitotoxins, and production of IL-1β and IL-6 and tumor necrosis factor [8]; the latter cytokines can have neurotrophic effects themselves [9,10]. Even the apparent benefits of NSAIDs can be parsed from their presumed mechanism of inhibiting cyclooxygenase-2 [12,13](and references therein)

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