HIPPOCAMPAL SYNAPTIC CONNECTIVITY IN ALZHEIMER'S DISEASE

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Alzheimer's disease (AD) is heralded by an irreversible decline in memory and cognitive function which is intensified until death. This severe impairment of brain functioning can be explained, at least in part, by pathological changes in nerve cells (neurofibrillary tangles, neuritic plaques, granulovacuolar degeneration and neuronal loss) typical of AD. It is conceivable, however, that a loss of synapses, which is not necessarily associated with neuronal loss, may contribute to the marked memory dysfunction in AD. Previous attempts to clarify this problem by quantifying neocortical synapses provided conflicting results, probably due to the use of inadequate technical approaches. It is also possible that structural synaptic modifications other than a loss of synapses may underlie the progressive memory deficit in AD. Of special importance in this regard is the extent of the synaptic active zone where the actual transmission of impulses is believed to take place. A reduction of this zone, which would be expected to hamper synaptic transmission, may occur in AD. So far, no attempt had been made to verity the validity of this suggestion. Therefore, the proposed work has been designed to elucidate, with the aid of modern stereological and morphometric techniques, if the number of synapses that involve surviving neurons and the extent of their active zone are reduced in AD. Synapses will be analyzed in the hippocampal formation, since this structure provides and essential link for registration of new experience and since it is markedly affected by the histopathological lesion characteristic of AD. The motor cortex will also be examined in order to determine whether structural synaptic alterations, if they occur in AD, are specific for the hippocampal synaptic contact, the so called perforated synapse, appears to be necessary for the maintenance of normal memory function. For this reason, a differential analysis of various synaptic types will be performed. The proposed research has a potential of providing important information concerning the possible impairment of synaptic connections in AD.