Neuroinflammation and tumor necrosis factor signaling in the pathophysiology of Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects nearly one in two individuals over 90 years of age. Its neuropathological hallmarks are accu-mulation of extraneuronal plaques of amyloid-beta (Aβ), the presence of neurofi brillary tangles formed by aberrantly hyperphosphorylated tau, progressive synaptic loss, and neurodegeneration which eventually results in decline of memory and cognitive faculties. Although the etiology of sporadic AD in humans is unknown, mutations in amyloid precursor protein or components of its processing machinery (β-secretase and γ-secretase) result in overproduction of Aβ1–40 and 1–42 peptides and are suffi cient to cause disease. In this review, we highlight the experimental and clinical evidence that suggests a close association between neuroinfl ammation and AD pathogenesis. Overproduction of infl ammatory mediators in the brain occurs when microglia, which are often found in close physical association with amyloid plaques in AD brains, become chronically activated. It has been proposed that elevated levels of pro-infl ammatory cytokines, including tumor necrosis factor (TNF), may inhibit phagocytosis of Aβ in AD brains thereby hindering effi cient plaque removal by resident microglia. In support of this idea, the bacterial endotoxin lipopolysaccharide, a potent trigger of infl ammation that elicits production of TNF and many other cytokines, can accelerate the appearance and severity of AD pathology in several animal models of AD. We review the evidence implicating TNF signaling in AD pathology and discuss how TNF-dependent processes may contribute to cognitive dysfunction and acceler-ated progression of AD. We conclude by reviewing the observations that provide compelling rationale to investigate the extent to which new therapeutic approaches that selectively target the TNF pathway modify progression of neuropathology in pre-clinical models of AD as well as the promising fi ndings with the use of nonsteroidal anti-infl ammatory drugs and recent clinical trials with Aβ immunotherapy.