Neuroinflammation in Alzheimer's disease: mechanisms, pathologic consequences, and potential for therapeutic manipulation

Abstract

The concept of neuroinflammation has evolved over the past two decades from an initially controversial viewpoint to its present status as a generally accepted idea whose mechanisms and consequences are still actively under research and debate, particularly with regard to Alzheimer's disease (AD). This review summarizes the current status of neuroinflammation research as it specifically relates to AD. Neuroinflammation is discussed mechanistically with emphasis on the role of redox signal transduction linked to the activation of central nervous system-relevant innate immune pathways. Redox signaling is presented both as a causal factor and a consequence of sustained neuroinflammation. Functional relationships are discussed that connect distinct neuroinflammatory components such as cytokines, eicosanoids, classic AD pathology (amyloid plaques and neurofibrillary tangles), and the recently emergent notion of "damage-associated molecular patterns". The interaction of these paracrine factors likely can produce positive as well as negative effects on the AD brain, ranging from plaque clearance by microglia in the short term to glial dysfunction and neuronal compromise if the neuroinflammation is chronically sustained and unmitigated. Recent disappointments in AD clinical trials of anti-inflammatory drugs are discussed with reference to possible explanations and potential avenues for future pharmacological approaches to the disease.

Fig. 1

A Representation of the glutathionylation cycle of protein regulation through glutathione conjugation, a principal means of redox signal transduction control at the level of post-translational modification. The protein modified by glutathionylation is typically (but not always) a phosphatase containing an especially nucleophilic cysteine. B) A broader view of the relationships amongst the phenomena of redox signal transduction, oxidative stress, and neuroinflammation. The hypothetical cell in this schematic is intended to be a microglial or astrocyte, which would be involved in reciprocal autocrine and paracrine signaling with ambient neurons and other glial cell types. The glutathionylation cycle depicted in panel A would be implicit in panel B, along with other types of reversible and irreversible protein post-translational modifications that mediate redox signal transduction mechanisms. In the context of AD specifically, perturbations in the intracellular signaling pathways would lead to aberrant phosphorylation, protein aggregation, and processing that could contribute ultimately to both NFTs and amyloid plaque deposition. These phenomena would superimpose upon and interact with the neuroinflammatory forces depicted explicitly in panel B.