Fig. 4

Role of PICALM in autophagy and the degradation of tau fibrils. The catabolic autophagy cascade engulfs cytoplasmic content such as dysfunctional organelles, aggregated proteins or peptides for degradation in lysosomes. Autophagy can be initiated through different upstream (metabolic) signals that converge into the activation of two protein complexes, the ULK complex (ATG13, ATG101, FIP200 and ULK1) and the VPS34 complex (Atg6, Atg14, VPS15 and VPS34). One of the first steps is the formation of the phagophore that recruits ubiquitinated cargo through receptor proteins like p62 as well as LC3. After closure, a double-membrane autophagosome is formed that next can fuse with lysosomes to form autophagolysosomes: this fusion provides the acidic environment and hydrolases to degrade engulfed cellular material. In (LO)AD, Tau gets hyperphosphorylated, which promotes its aggregation into fibrils that are targeted by the cell for autophagic breakdown. The pathway requires Tau to be ubiquitinated by the CHIP (carboxyl terminus of the Hsc70-interacting protein)-Hsc70 complex. Under normal circumstances autophagy can keep pace with the breakdown of Tau aggregates. When this process gets impaired, as occurs in the AD pathology, Tau aggregates cannot be cleared and start to build up, resulting in the formation of neurofibrillary tangles in the end. PICALM dysregulation in LOAD could affect its normal functioning; the interaction and endocytosis of SNARE proteins by PICALM, e.g. VAMP2, VAMP3 and VAMP8, regulates the autophagy process and, hence, removal of Tau. Moreover, through PICALM’s interaction with the complex adaptor protein 2 (AP2), it cross-links LC3 to the APP C-terminal fragment that makes the fragment to be taken up and broken down in the autolysosome