Increasing evidence supports that cellular dysregulations in the degradative routes contribute to the initiation and progression of neurodegenerative diseases, including Alzheimer’s disease. Autophagy and endolysosomal homeostasis need to be maintained throughout life as they are major cellular mechanisms involved in both the production of toxic amyloid peptides and the clearance of misfolded or aggregated proteins. As such, alterations in endolysosomal and autophagic flux, as a measure of degradation activity in these routes or compartments, may directly impact as well on disease-related mechanisms such as amyloid-β clearance through the blood-brain-barrier and the interneuronal spreading of amyloid-β and/or Tau seeds, affecting synaptic function, plasticity and metabolism. The emerging of several genetic risk factors for late-onset Alzheimer’s disease that are functionally related to endocytic transport regulation, including cholesterol metabolism and clearance, supports the notion that in particular the autophagy/lysosomal flux might become more vulnerable during ageing thereby contributing to disease onset. In this review we discuss our current knowledge of the risk genes APOE4, BIN1, CD2AP, PICALM, PLD3 and TREM2 and their impact on endolysosomal (dys)regulations in the light of late-onset Alzheimer’s disease pathology.

A particularly interesting marker to identify anti-tumor immune cells is the neural cell adhesion molecule (NCAM), also known as cluster of differentiation (CD)56. Namely, hematopoietic expression of CD56 seems to be confined to powerful effector immune cells. Here, we sought to elucidate its role on various killer immune cells. First, we identified the high motility NCAM-120 molecule to be the main isoform expressed by immune cells. Next, through neutralization of surface CD56, we were able to (1) demonstrate the direct involvement of CD56 in tumor cell lysis exerted by CD56-expressing killer cells, such as natural killer cells, gamma delta (γδ) T cells, and interleukin (IL)-15-cultured dendritic cells (DCs), and (2) reveal a putative crosstalk mechanism between IL-15 DCs and CD8 T cells, suggesting CD56 as a co-stimulatory molecule in their cell-to-cell contact. Moreover, by means of a proximity ligation assay, we visualized the CD56 homophilic interaction among cancer cells and between immune cells and cancer cells. Finally, by blocking the mitogen-activated protein kinase (MAPK) pathway and the phosphoinositide 3-kinase (PI3K)–Akt pathway, we showed that IL-15 stimulation directly led to CD56 upregulation. In conclusion, these results underscore the previously neglected importance of CD56 expression on immune cells, benefiting current and future immune therapeutic options.