Many of the studies investigating morphological substrates underlying the progressive AD dementia involved the hippocampal formation and specifically the molecular layer of the hippocampal dentate gyrus. The granule cell dendrites in the outer molecular layer (OML) of the dentate gyrus receive a very significant input from the ipsilateral entorhinal cortex, an area that is noted for its abundance of NFT-containing cells in AD. Immunohistochemical studies have concentrated on this region and reported significant declines in synaptophysin immunostaining ranging from 11% to 77%23,56,59,68-70,74-76. in two ultrastructural investigations, the actual number of synapse was counted in the molecular layer in both AD and age-matched controls. Ten short PMI (<8 h) nondemented control subjects were compared to age and PMI-matched AD subjects who had illness duration of approximately 9 years, indicative of end stage in the disease. A stereological sampling scheme was used to estimate the packing density of synapses in both the OML and inner molecular layer (IML). A significant 21% loss of synapses in the OML and a 15% decline in the IML was observed77,78. Along with these findings was a significant (26%) decline in the width of the dentate gyrus molecular layer in the AD group that could impact upon the synaptic packing density resulting in an underestimation of the total synaptic loss. The decline in the IML is particularly interesting since it supports the idea that the entire hippocampal formation is significantly affected29,68,69. This region of the dentate gyrus does not receive any direct input from the ERC but rather intrahippocampal connectivity.
The synaptic decline in the OML might be viewed as a reduction in hippocampal plasticity that occurs in the end- stage of the disease46,79. A very recent paper indicates that this region of the hippocampus fails to replace lost synaptic contacts even in the very early stages of the disease process80. If this region is vulnerable and fails to maintain a normal complement of synapses, it might explain some of the short-term memory changes observed in individuals with mild cognitive impairment. Two of the previously mentioned ultrastructural studies of the frontal cortex were carried out in biopsy samples from individuals in the early stages of the disease17,47. Both studies reported significant synapse loss, again supporting the idea that a decline in synaptic plasticity may be an early event and account for some of the dementia.
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