Alzheimer’s is a progressive neurodegenerative disease characterized by memory loss, difficulty in speech, interference and inability to do day to day activities. As it is a progressive disorder with time it gets worsened and brain gets damaged due to neuronal cell death. In Alzheimer’s synaptic transmissions do not occur to transmit the signals due to the build-up of protein plaques called beta amyloid. It is the most common type of dementia, of about 60-80% of dementia is occurred by Alzheimer’s disease.

Alzheimer’s disease is the most common form of dementia, characterized by a persistent and progressive impairment of cognitive functions. Alzheimer’s disease is typically associated with extracellular deposits of amyloid-β peptide and accumulation of abnormally phosphorylated tau protein inside neurons (amyloid-β and neurofibrillary pathologies). It has been proposed that these pathologies cause neuronal degeneration and synaptic alterations, which are thought to constitute the major neurobiological basis of cognitive dysfunction in Alzheimer’s disease. The hippocampal formation is especially vulnerable in the early stages of Alzheimer’s disease. However, the vast majority of electron microscopy studies have been performed in animal models. In the present study, we performed an extensive 3D study of the neuropil to investigate the synaptic organization in the stratum pyramidale and radiatum in the CA1 field of Alzheimer’s disease cases with different stages of the disease, using focused ion beam/scanning electron microscopy (FIB/SEM). In cases with early stages of Alzheimer’s disease, the synapse morphology looks normal and we observed no significant differences between control and Alzheimer’s disease cases regarding the synaptic density, the ratio of excitatory and inhibitory synapses, or the spatial distribution of synapses. However, differences in the distribution of postsynaptic targets and synaptic shapes were found. Furthermore, a lower proportion of larger excitatory synapses in both strata were found in Alzheimer’s disease cases. Individuals in late stages of the disease suffered the most severe synaptic alterations, including a decrease in synaptic density and morphological alterations of the remaining synapses. Since Alzheimer’s disease cases show cortical atrophy, our data indicate a reduction in the total number (but not the density) of synapses at early stages of the disease, with this reduction being much more accentuated in subjects with late stages of Alzheimer’s disease. The observed synaptic alterations may represent a structural basis for the progressive learning and memory dysfunctions seen in Alzheimer’s disease cases.

Human brain samples from five subjects with no recorded neurological or psychiatric alterations (considered to be a control group) and five cases with different degrees of Alzheimer’s disease pathology according to Braak stage and CERAD neuropathological diagnosis were obtained following the guidelines of the Institutional Ethical Comitte. The post-mortem delay was lower than 4.5 h in all cases. See further details in the Supplementary material for sample source and tissue processing, and immunohistochemistry

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