O1-01-02: Mitochondrial alterations in relation to synaptic pathology in Alzheimer’s disease

Abstract

hippocampus in AD. Individuals with MCI, lacking a clinical diagnosis of AD, manifest a decline in synapse numbers in the hippocampus. It is unclear whether areas of neocortex also affected in AD display synaptic loss during this prodromal transitional stage. The inferior temporal gyrus (ITG) is considered tertiary association cortex with a special role in higher order visual function. It is an integral part of the visual association pathway that provides the anatomical substrate for the perception and memory of shapes and objects. Objective: To assess total synaptic numbers in lamina III of the ITG during the progression of AD. Methods: Tissue was examined from the Rush Religious Orders Study and from the AD Center at the University of Kentucky. All cases had detailed clinical evaluation within 12 months prior to death and were categorized as AD, MCI, or no cognitive impairment (NCI). Systematic random samples throughout the entire extent of the ITG were obtained at autopsy and processed for standard transmission electron microscopy. Unbiased stereological techniques employing the physical disector were used to estimate the total number of synapses in lamina III. Results: Preliminary results revealed that the AD group had significantly fewer synapses than NCI. The mean number of synapses in the MCI group was also lower compared to NCI but higher than the AD subjects. The total volume of the ITG appeared the same for both the NCI and MCI cases; and substantially greater than the AD group volume. There was a highly significant association between the total number of synapses in the ITG and the subject’s score on the mini mental status exam (MMSE). Conclusions: This is the first study to estimate the total number of synapses in a specific region of the human neocortex. These results suggest that the ITG in individuals with MCI manifest synaptic loss that may be equivalent to some AD subjects, supporting the idea that significant synaptic loss occurs early in the progression to AD.