Alzheimer's disease (AD) manifests severe pathological changes in the CNS including increased levels of amyloid, hyperphosphorylated tau, and synaptic loss. Synaptic dysfunction is a hallmark of the disease that associates with the cognitive ability and level of dementia during the progression of AD. It is unclear why synaptic numbers are reduced in the early stages of AD and how it is linked to other features of the pathology. We believe that oxidative damage and microtubule/actin changes are early events in the progression of AD and underlie synaptic dysfunction. Increasing evidence suggests that the medial temporal lobe (MTL) is the earliest regions of the brain affected and may provide important clues to the progression of the disease. Our hypothesis is that multiple different cellular changes occur in the MTL initiating the loss of synaptic plasticity resulting in a declinein cognition and the onset of clinical AD. The proposed experiments will evaluate changes in this brain region in regards to synaptic proteins, oxidative stress, and structural proteins. Studies ar carried out on short post mortem samples from longitudinally followed individuals with detailed cognitive testing. Individuals with amnestic mild cognitive impairment (aMCI) will be compared to individuals that clinically show no cognitive impairment (NCI). The NCI group is further classified as individuals with very low pathology (LP- NCI) or high (AD levels) of histopathology (HP-NCI). Current literature suggests that HP-NCI represents individuals with preclinical AD.
Aim one assess the direct relationship between different key synaptic proteins and oxidative stress in the MTL.
Aim two probes whether or not NADPH-oxidase (NOX) activity and its subunits change during the disease progression and how it associates with changes in synaptic proteins and soluble A beta. The NOX enzyme is normally expressed throughout the central nervous system and is a key non-mitochondrial source of free radicals.
The third aim explores whether or not key cytoskeletal proteins, such as the actin binding protein cofilin and tau, increase in the MTL and alters different levels of key synaptic proteins. Successful completion of the proposed studies will reveal new insights into the mechanisms underlying the very early stages in the progression of AD and contribute to the development of rational therapies.

Public Health Relevance

Understanding cellular changes that occur in the early progression of AD will help to develop novel biomarkers for early detection. In addition it will help in designing specific novel therapies to slow or perhaps prevent the progression when detected early. The proposed studies are directly relevant to the mission of the NIA to support research aimed at understanding the cellular and clinical processes of dementia.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG042475-01A1
Application #
8509203
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Petanceska, Suzana
Project Start
2013-06-01
Project End
2018-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$307,244
Indirect Cost
$102,244
Name
University of Kentucky
Department
Other Health Professions
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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