Lipocalin 2: novel inflammatory actor in Alzheimer's disease

Inflammatory processes are of particular importance in Alzheimer's disease (AD). We identified Lipocalin 2 as a neuroinflammatory component that is increased during early stages of the disease and can play an important role in the pathogenesis of AD. Lipocalin 2 in the brain is a result of Tumor Necrosis Factor alpha (TNF‐α) signaling and high levels of Lipocalin 2 expression are found in brain regions with AD pathology. Contrary to other inflammatory proteins, Lipocalin 2 levels are strongly decreased in the cerebrospinal fluid (CSF) of Mild Cognitive Impaired (MCI) patients and AD patients, as compared to healthy subjects. In a large clinical cohort we found that Lipocalin 2 significantly increased in depressed elderly females with cognitive impairments, a population group at high risk to develop Alzheimer's disease. We also found that Lipocalin 2 is associated with distinct amyloid beta species related to the progression of dementia in Downs Syndrome. Mechanistically, Lipocalin 2 sensitizes neurons to the toxic effects of oligomeric forms of Aβ and silences the neuroprotective mechanisms by inhibiting TNF‐α mediated signaling via its receptor 2. The present study introduces Lipocalin 2 as a novel neuro‐immunopathogen in early clinical stages of AD. The clinical data suggest Lipocalin 2 as potential biomarker for early forms of AD, since dynamic alterations in expression of the protein appear to parallel disease progression. In addition, Lipocalin 2 may function as a (neuro)inflammatory marker linking late‐life depression and AD.