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Basic Research |
Basic Research Overview >
Study Details
| The roles of A-beta, tau, and synaptic loss in early AD |
Principal Investigator: Richard O'Brien, M.D., Ph.D. [ Bio ]
The accumulation of amyloid beta (A-beta) and tau as well as synaptic loss have all been implicated in the early stages of Alzheimer’s disease (AD). The overarching goal of this project is to understand the mechanisms that allow some individuals to tolerate substantial AD pathology, whereas others with similar brain abnormalities develop mild cognitive impairment (MCI) or dementia. This study is using brain tissue from subjects who were cognitively normal shortly before death, but were found to have substantial AD pathology on autopsy, as well as the brains from subjects with MCI and patients with AD. Aim 1: We will test the hypothesis that A-beta oligomers, not A-beta deposits, are responsible for cognitive decline. We will determine whether A-beta 40, A-beta 42 and A-beta oligomers distinguish the cognitive phenotypes of subjects with similar levels of AD pathology, as measured by the standard Braak and CERAD pathology rating scales. In addition, we will examine whether the significant A-beta accumulation seen in the brains of the subset of cognitively normal subjects with substantial AD pathology is due to quantitative differences in the amount, bioactivity or distribution of enzymes purported to degrade or transport A-beta in vivo. Aim 2: We will test the hypothesis that the process that couples A-beta deposition with neuronal/synaptic abnormalities is associated with Tau phosphorylation or cleavage. We propose to quantify the amount of Tau phosphorylation and fragmentation in brain specimens to determine the strength of the relationship between these biochemical changes and cognitive status. We will also examine whether quantitative differences in the regional distribution of A-beta monomers, A-beta oligomers or glycogen synthetase kinase (GSK) 3a and 3b are associated with Tau phosphorylation or cleavage. Aim 3: On the assumption that synaptic dysfunction and degeneration underlies the cognitive impairment in AD, we will test the hypothesis that enhanced synaptic plasticity allows for normal cognition in the face of significant AD pathology.
For more information, contact Richard O’Brien at robrien@jhmi.edu.
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