Cellular Changes Altering Synaptic Connectivity in PreClinical AD

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 connectivity resulting in a decline in 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 are carried out on short post motem 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 (LP-NCI) pathology or high (AD levels) of histopathology (HP-NCI). Current literature suggests that this HP-NCI cohort represents individuals with preclinical AD (PCAD). Aim one assess the direct relationship between different markers of oxidative stress and key synaptic proteins in the MTL and the relationship to the subject's cognitive scores. Aim two probes whether or not NADPH-oxidase (NOX) and its subunits associates with changes in synaptic proteins. 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. 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.