Search

Numerous studies have reported widespread synaptic dysfunction or loss in early stages of both Alzheimer disease (AD) patients and animal models; it is widely accepted that synapse loss is the major structural correlate of cognitive dysfunction. Elucidation of the changes that may affect synapses is crucial for understanding the pathogenic mechanisms underlying AD, but ultrastructural preservation of human postmortem brain tissue is often poor, and classical methods for quantification of synapses have significant technical limitations. We previously observed changes in dendritic spines in plaque-free regions of the neuropil of the dentate gyrus of double-transgenic APP/PS1 (amyloid precursor protein/presenilin 1) model mice by light microscopy. Here, we used electron microscopy to examine possible synaptic alterations in this region. We used standard stereologic techniques to determine numbers of synapses per volume. We were able to reconstruct and analyze thousands of synapses and their 3-dimensional characteristics using a focused ion beam/scanning electron microscope and 3-dimensional reconstruction software (EspINA), which performs semiautomated segmentation of synapses. Our results show that both numbers of synapses per volume and synaptic morphology are affected in plaque-free regions of APP/PS1 mice. Therefore, changes in the number and morphology of synapses seem to be widespread alterations in this animal model.

The main hallmarks of human hippocampal sclerosis are neuronal loss and gliosis; reductions in microvasculature labeling in the cornu Ammonis 1 in this condition have been detected using alkaline phosphatase histochemistry. To determine whether the reduction inalkaline phosphatase activity is coupled with a loss of blood vessels,we examined the volume fraction occupied by blood vessels in toluidine blue-stained hippocampal sections from 24 epilepsy patientresections (19 with hippocampal sclerosis, 5 without hippocampal sclerosis) and 5 normal autopsy controls. Light and electron microscopy and immunohistochemistry were used to determine the distribution of collagen Type IV in relation to the fine structure of the hippocampal microvascular network. We found a consistent and highly significant loss of microvessels in the sclerotic hippocampal cornu Ammonis 1 field; a variety of vascular alterations including spinelike protrusions, disruptions, and atrophic branching, were observed in the remaining blood vessels. We suggest that blood vessel alterations are an additional pathological hallmark of hippocampal sclerosis associated with temporal lobe epilepsy and that they may relate to the pathogenesis of this condition.