TY - JOUR T1 - 3D Electron Microscopy study of synaptic organization of the normal human transentorhinal cortex and its possible alterations in Alzheimer’s disease JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0140-19.2019 SP - ENEURO.0140-19.2019 AU - M Domínguez-Álvaro AU - M Montero-Crespo AU - L Blazquez-Llorca AU - J DeFelipe AU - L Alonso-Nanclares Y1 - 2019/06/19 UR - http://www.eneuro.org/content/early/2019/06/19/ENEURO.0140-19.2019.abstract N2 - The transentorhinal cortex (TEC) is an obliquely oriented cortex located in the medial temporal lobe and, together with the entorhinal cortex, is one of the first affected areas in Alzheimer’s disease (AD). One of the most widely accepted hypothesis is that synaptopathy (synaptic alterations and loss) represents the major structural correlate of the cognitive decline observed in AD. However, very few electron microscope studies are available; the most common method to estimate synaptic density indirectly is by counting —at the light microscopic level— immunoreactive puncta using synaptic markers.To investigate synaptic morphology and possible alterations related to AD, a detailed three-dimensional (3D) ultrastructural analysis using focused ion beam/scanning electron microscopy (FIB/SEM) was performed in the neuropil of layer II of the TEC in human brain samples from non-demented subjects and AD patients. Evaluation of the proportion and shape of asymmetric and symmetric synapses (AS and SS, respectively) targeting spines or dendritic shafts was performed using 3D reconstructions of every synapse. The 3D analysis of 4722 synapses revealed that the preferable targets were spine heads for AS and dendritic shafts for SS, both in control and AD cases. However, in AD patients, we observed a reduction in the percentage of synapses targeting spine heads. Regarding the shape of synapses, in both control cases and AD samples, the vast majority of synapses had a macular shape, followed by perforated or horseshoe-shaped synapses, with fragmented synapses being the least frequent type. Moreover, comparisons showed an increased number of fragmented AS in AD patients.Significance Statement Determination of postsynaptic targets, shape and size of the synaptic junctions provide critical data on synaptic functionality. However, as far as we know, detailed 3D synaptic morphology and identification of postsynaptic targets in serial sections have not been performed before in the human brain. The present study represents the first attempt to unveil the synaptic organization of the neuropil of the human brain at the ultrastructural level using 3D electron microscopy. Our present results provide a new, large, quantitative ultrastructure dataset of the synaptic organization of the normal human cortex and of the synaptic alterations that occur in AD. Thus, these results may help to understand the relationship between alterations of the synaptic circuits and the cognitive deterioration in AD. ER -