BackgroundInterleukin-1 beta (IL-1β) and its key regulator, the inflammasome, are suspected to play a role in the neuroinflammation observed in Alzheimer’s disease (AD); no conclusive data are nevertheless available in AD patients.ResultsmRNA for inflammasome components (NLRP1, NLRP3, PYCARD, caspase 1, 5 and 8) and downstream effectors (IL-1β, IL-18) was up-regulated in severe and MILD AD. Monocytes co-expressing NLRP3 with caspase 1 or caspase 8 were significantly increased in severe AD alone, whereas those co-expressing NLRP1 and NLRP3 with PYCARD were augmented in both severe and MILD AD. Activation of the NLRP1 and NLRP3 inflammasomes in AD was confirmed by confocal microscopy proteins co-localization and by the significantly higher amounts of the pro-inflammatory cytokines IL-1β and IL-18 being produced by monocytes. In MCI, the expression of NLRP3, but not the one of PYCARD or caspase 1 was increased, indicating that functional inflammasomes are not assembled in these individuals: this was confirmed by lack of co-localization and of proinflammatory cytokines production.ConclusionsThe activation of at least two different inflammasome complexes explains AD-associated neuroinflammation. Strategies targeting inflammasome activation could be useful in the therapy of AD.

An impairment of the microglial catabolic mechanisms allows amyloid-β (Aβ) accumulation in plaques within the brain in Alzheimer's disease (AD). Monocytes/macrophages (M/M) are activated in AD and migrate thorough the blood-brain barrier (BBB) trying to improve Aβ clearing. In the attempt to shed light on the role of M/M in AD, these cells were analyzed in patients with AD or mild cognitive impairment (MCI) and in age-matched healthy controls. Results obtained in Aβ42-stimulated cell cultures showed that significantly higher percentages of inflammatory M/M (CD14+ CD16-CCR2++CX3CR1low) expressing toll like receptors (TLR) 2 and 4, as well as IL-6 and CCR2, a chemokine favoring M/M migration through the BBB, are seen in AD. Confocal microscopy suggested the presence of MHC-II/Aβ42 complexes on AD M/M alone. Finally, TRL3- and TLR8-expressing and IL-23-producing M/M were increased in both AD and MCI compared to HC. These data indicate that M/M in AD are characterized by an inflammatory profile and are involved in the induction of both innate immune responses via TLR stimulation and of acquired immunity possibly secondarily to the presentation of Aβ peptides in an MHC-restricted fashion. Therapeutic approaches designed to interrupt these mechanism might prove beneficial.

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