Inflammation in Alzheimer's disease: relevance to pathogenesis and therapy

In addition to amyloid beta (Aβ) and tau protein aggregates, the presence of immune-related antigens and cells around amyloid plaques in the brains of patients with Alzheimer's disease (AD) has been reported since the 1980s [1-3]. These initial observations brought about changes to the previously assumed view of the brain as an immunologically isolated organ. In the 1990s, additional findings of activated complement factors, cytokines and a wide range of related receptors in the brain of AD patients led to the concept of neuroinflammation (inflammation within the central nervous system (CNS)), which suggests that immunological processes in the brain are likely to be involved in the pathology of degenerative diseases of the CNS. Table 1 lists signs of an altered immune response reported in AD patients.The role of aggregated proteins in the pathology of AD had to be re-considered to account for these observations. The inflammation hypothesis emerged relatively recently, when it became clear that the observations of altered immune processes in AD could not be ignored. Neuroinflammation is still considered to be a downstream consequence in the amyloid hypothesis, with Aβ amyloid within the CNS bringing about activation of microglia, initiating a pro-inflammatory cascade that results in the release of potentially neurotoxic substances, including cytokines, chemokines, reactive oxygen and nitrogen species, and various proteolytic enzymes, leading to degenerative changes in neurons [4-7]. It has also been suggested that activation of microglia may lead to phosphorylation of tau and formation of neurofibrillary tangles (NFTs) [8-10]. However, the exact role of inflammation in the pathology of AD and its mechanisms in terms of the cells involved - microglia, astrocytes and T lymphocytes - are still debated.The inflammation hypothesis is also supported by epidemiological retrospective observations that patients with rheumatoid disease who are on long-term anti-inflammatory th