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

Journal of Neuroinflammation BioMed Central Commentary Open Access Vascular consequences of passive Aβ immunization for Alzheimer's disease. Is avoidance of "malactivation" of microglia enough? Steven W Barger*1,2,3 Address: 1Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205 USA, 2Department of Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205 USA and 3Geriatric Research Education and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205 USA Email: Steven W Barger* - * Corresponding author Published: 11 January 2005 Journal of Neuroinflammation 2005, 2:2 doi:10.1186/1742-2094-2-2 Received: 03 January 2005 Accepted: 11 January 2005 This article is available from: http://www.jneuroinflammation.com/content/2/1/2 © 2005 Barger; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract 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. Introduction Alzheimer's disease (AD) is a progressive degeneration of neural structure and function that arises in the cerebral cortex. Behaviorally, affected individuals usually present with semantic difficulty, followed by a deficiency in episodic memory, spatial disorientation, sleep disturbances, depression, agitation, loss of longer memories, general difficulty with the activities of daily living, and eventually, death. Neuropathological findings include a relatively high number of extracellular deposits of the amyloid βpeptide (Aβ), argyrophillic cytoskeletal aggregates in neu- rons, accumulation of α-synuclein, loss of synapses, loss of cholinergic and adrenergic fibers, loss of pyramidal neurons, and cerebral amyloid angiopathy (CAA) – deposition of Aβ around blood vessels. Most of the AD correlates above have been connected in some way to inflammation. For instance, the plaques – comprised primarily of aggregated amyloid β-peptide (Aβ) – are inundated with microglia that show profiles of morphology and gene expression consistent with inflammation. Indeed, if one characterizes any activity by microPage 1 of 4 (page number not for citation purposes) Journal of Neuroinflammation 2005, 2:2 glia as a sign of "neuroinflammation," it can be said that inflammatory responses have been evident in AD for at least 40 years [1]. But, 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. Recognition of the powerful impact of a cytokine like interleukin-1 (IL-1), elevated in AD microglia, permitted such speculation [2]. Similarly, research accrued showing that primary inflammation could lead to many of the aberrations found in AD, fueling the consideration that inflammatory events were seminal [3-5]. Many of the individual molecules produced by activated microglia and astrocytes are conditional neurotoxins: hydrogen peroxide, glutamate and other agonists of glutamate receptors, complement components, prostanoids. (Nitric oxide from inducible nitric oxide synthase, produced abundantly in rodent glia, may be less important in human tissues.) Retrospective epidemiological studies showed protection against AD – either in age of onset or rate of progression – by nonsteroidal antiinflammatory drugs (NSAIDs); such correlations have now been born out in a prospective study [6]. Perhaps most compelling, polymorphisms in the genes for proinflammatory cytokines are indicative of risk for AD [7]. Despite these indications, there are reasons to believe that the changes observed in glia and inflammatory cytokines constitute a compensatory response in AD. Indeed, some investigators have been reluctant to apply the term "inflammation" to the constellation of events related to AD pathology. Some of the cytokines and other gene products expressed in peripheral sites of inflammation are present in the AD brain, but there is no apparent vasodilation or extravasation of neutrophils. In general, there seems to be less of the molecular and cellular behavior that is responsible for bystander tissue damage in peripheral inflammation. This journal was founded partially out of recognition that "neuroinflammation" is distinct. In essence, the concept reflects a compromise befitting the difficult line that must be maintained between effective cell-mediated immune responses and damage to the precious components of the CNS. 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]; in fact, the latter cytokines can have neurotrophic effects themselves [9,10]. Astrocytes deposit proteoglycans around the Aβ deposits destined to become plaques [11], perhaps sequestering this neurotoxic peptide from doing its harm. Even the apparent benefits of NSAIDs can be parsed from their presumed mechanism of inhibiting cyclooxygenase-2 [12,13](and references therein). http://www.jneuroinflammation.com/content/2/1/2 Discussion Recent experiments with anti-Aβ immunization have highlighted another beneficial effect of "activated (...truncated)