In clathrin-mediated endocytosis (CME), the main route for APP incorporation into clathrin-coated vesicles at the plasma membrane, and PICALM, a Phosphatidylinositol-binding clathrin assembly key protein, reducing PICALM expression diminishes APP internalization and lowers Aβ production [71], and abnormal cleavage of PICALM is also associated with neurofibrillary tangles, co-localizing with abnormally structured tau and increased tau phosphorylation (p-tau), contributing to AD intracellular dysfunction [71, 73]. Here, APP is linked to Neurofibrillary tangles.