A number of studies have reached similar conclusions concerning the relationship between neocortical NFTs and cognitive impairment. During the initial phase of the syndrome, NFTs are restricted to the entorhinal cortex, progressively spreading to the limbic and medial temporal lobe and correlating with early AD symptoms related to memory [10, 11]. At the end stage, NFTs are more abundant and found in neocortical regions involved in executive function, visual and spatial abilities, and language, skills that are impaired in advanced state AD patients [12, 13]. While it is almost impossible to recapitulate the whole process in vitro, models of AD based on cultured neurons are likely to capture at least some key features of early-stage pathology, especially neuronal generation of Aβ. Yet standard primary neuronal cultures poorly represent the environment of central nervous system since they typically exclude glial cells and the complex 3-dimensional (3D) architecture of cerebral cortex. Modeling the spatial and temporal pathogenic events in a 2 dimensional (2D) cultured cell system seems almost impossible in light of the complexity of 3D neuronal structure enclosed in a human brain.
