Mounting evidence suggests that individuals with mild cognitive impairment (MCI) 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 loss 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 (Abeta) and oxidative damage may be fundamentally involved in the pathogenesis of AD and contribute to MCI. The interaction between Abeta, oxidative damage and synapse loss may provide important keys to the mechanisms that lead to MCI. This proposal will examine the hypothesis that synapse loss is associated with cognitive deficits observed in the early phase of the disease process, and is responsible for amnestic memory problems associated with MCI. 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 Abeta is considered by many researchers to play an important role in progression of AD, we will study the relationship of soluble Abeta1-42 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 Ap and oxidative stress and are important for synapse function. Successful completion of the proposed studies will lead to new insights into the mechanisms underlying MCI and early AD and contribute to the development of effective pharmacologic therapies for AD. ? ? ?
| Smith, Vanessa D; Bachstetter, Adam D; Ighodaro, Eseosa et al. (2018) Overlapping but distinct TDP-43 and tau pathologic patterns in aged hippocampi. Brain Pathol 28:264-273 |
| Scheff, Stephen W; Price, Douglas A; Ansari, Mubeen A et al. (2015) Synaptic change in the posterior cingulate gyrus in the progression of Alzheimer's disease. J Alzheimers Dis 43:1073-90 |
| Scheff, Stephen W; Neltner, Janna H; Nelson, Peter T (2014) Is synaptic loss a unique hallmark of Alzheimer's disease? Biochem Pharmacol 88:517-28 |
| Scheff, Stephen W; Price, Douglas A; Schmitt, Frederick A et al. (2013) Synapse stability in the precuneus early in the progression of Alzheimer's disease. J Alzheimers Dis 35:599-609 |
| Schmitt, Frederick A; Nelson, Peter T; Abner, Erin et al. (2012) University of Kentucky Sanders-Brown healthy brain aging volunteers: donor characteristics, procedures and neuropathology. Curr Alzheimer Res 9:724-33 |
| Riley, Kathryn P; Jicha, Gregory A; Davis, Daron et al. (2011) Prediction of preclinical Alzheimer's disease: longitudinal rates of change in cognition. J Alzheimers Dis 25:707-17 |
| Ansari, Mubeen A; Scheff, Stephen W (2011) NADPH-oxidase activation and cognition in Alzheimer disease progression. Free Radic Biol Med 51:171-8 |
| Scheff, Stephen W; Price, Douglas A; Schmitt, Frederick A et al. (2011) Synaptic loss in the inferior temporal gyrus in mild cognitive impairment and Alzheimer's disease. J Alzheimers Dis 24:547-57 |
| Saijo, Eri; Scheff, Stephen W; Telling, Glenn C (2011) Unaltered prion protein expression in Alzheimer disease patients. Prion 5:109-16 |
| Ansari, Mubeen A; Scheff, Stephen W (2010) Oxidative stress in the progression of Alzheimer disease in the frontal cortex. J Neuropathol Exp Neurol 69:155-67 |
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