Targeting TNFSF10 as a novel immunotherapeutic strategy in Alzheimer’s disease

Alzheimer’s disease (AD) is the most common cause of dementia worldwide, characterized by extreme unmet needs and a huge disease burden. Cerebral atrophy, amyloid plaques, and neurofibrillary tangles represent the main pathological characteristics of the AD brain. Despite remarkable research efforts to unravel pathophysiological mechanisms of AD, a disease-modifying therapeutic option is still today far from clinical practice, as numerous phase III clinical trials targeting amyloid-beta (Aβ) and other disease markers have failed to improve clinical outcomes of AD patients enrolled. The identification of reliable biomarkers that reflect disease progression is crucial to design disease-modifying therapies able to act at its earliest preclinical stage for better management of AD patients. Elevated levels of inflammatory markers in patients with AD and the identification of AD risk genes associated with innate immune functions suggest that inflammation holds a crucial role in AD pathogenesis, implying that immune pathways could represent therapeutic targets. In this line, inflammatory cytokines are actively involved in AD pathogenesis and may serve as diagnostic or therapeutic targets to keep track of AD-related neurodegeneration. Since a physiologic immune response appears crucial to ensure maintenance of a healthy brain, this research project has focused on Tumor Necrosis Factor Apoptosis-Inducing Ligand (TRAIL), also named as TNFSF10, a cytokine belonging to the TNF superfamily, involved in the pathogenesis of several disorders and, in particular, in the AD-related inflammatory processes. Taking into account such hypothesized prominent role of immune response in AD, a first objective of the project has been testing whether chronic immunoneutralization of TNFSF10 could imply a re-balance of both central and peripheral immune response and whether this could relate to the decreased Aβ burden in the brain of 3xTg-AD mice, a transgenic strain resembling human AD pathology and already known to display improvement of functional outcome following treatment with an anti-TNFSF10 monoclonal antibody. Neutralization of TNFSF10 resulted in a significantly reduced expression of an array of immune/inflammatory markers, including those typical of peripheral T cells subgroup referred to as T regulatory cells, and restraint of microglial activity, paralleled by dramatically decreased burden of Aβ and p-Tau. Consistently, overshoot of splenic inflammatory/immune parameters associated with parenchymal amyloidosis were shut down as a consequence of the treatment. In the attempt to assess a suitable model to identify AD in its early phases, the second objective of the study was to investigate in 3xTg-AD mice the role of the TNFSF10 system and miRNAs usually associated to neuroinflammatory processes in the retina, a tissue regarded as an extension of the central nervous system. To accomplish this task, the focus was made on a set of miRNAs, linked to both AD and age-related macular degeneration (AMD). Specific age-related miRNA dysregulation was found in the retina of 3xTg-AD mice in a way related to the TNFSF10 signaling pathway, as assessed by bioinformatic analysis. The whole miRNA/TNFSF10 network was shut down following chronic TNFSF10 immunoneutralizing treatment, paralleled by a dramatic improvement of both tissue and inflammatory parameters in the retina of 3xTg-AD mice. In conclusion, immunopharmacological modulation of TNFSF10 brings about significant amelioration of the AD pathology, suggesting that therapeutic exploitation of TNFSF10 signaling represents a novel strategy for effective treatment of AD and related phenomena.