Synaptic Change in Mild Cognitive Impairment

Mounting evidence suggests that individuals with mild cognitive impairment (MC!) have an increased likelihood to develop Alzheimer's disease (AD), It is unclear what early pathophysiological changes may underlie this transition, The brains of individuals with definite AD manifest several pathological changes including a substantial/oss of synapses in association areas of the neocortex, Recent work has now demonstrated that synaptic loss provides an excellent correlation with cognitive ability and provides a strong correlate of dementia, The relationship between synapse loss, early cognitive decline, such as that observed in MCI, is poorly understood, There is increasing evidence that amyloid beta peptide (AP) and oxidative damage may be fundamentally involved in the pathogenesis of AD and contribute to MC!. The interaction between A0, oxidative damage and synapse loss may provide important keys to the mechanisms that lead to MC!. This proposal will examine the hypothesis that synapse loss is associated with cOQnitive deficits observed in the earlv phase of the disease process, and is responsible for amnestic memory problems associated with MC!. Studies will be carried out on short postmortem interval brains from individuals characterized as no cognitive impairment (NCI), MCI, and early AD, and evaluation of total synapses will be obtained by coupling unbiased stereology with transmission electron microscopy, Since AJ3is considered by many researchers to play an important role in progression of AD, we will study the relationship of soluble AJ3I-42 with synaptic loss and pre/post synaptic proteins, The specific aims will also test the hypothesis that oxidative damage is an early indicator of MCI and is associated with changes in total synaptic numbers in neocortical association areas known to be affected early in AD, Finally, we will study possible changes in mitochondrial bioenergetics that occur in MCI and early AD since mitochondria can be affected by both AJ3 and oxidative stress and are important for synapse function, Successful completion of the proposed studies will/ead to new insights into the mechanisms underlying MCI and early AD and contribute to the development of effective pharmacologic therapies for AD,