Project 2 in the Johns Hopkins Alzheimer's Disease Research Center (ADRC) is entitled """"""""The roles of AB, tau and synaptic loss in early AD"""""""". The overarching goal of this project is to understand the mechanisms that allow some individuals to tolerate substantial Alzheimer's disease (AD) pathology, whereas others with similar brain abnormalities develop MCI or dementia. We will use a collection of brains from prospectively followed subjects from the ADRC, known as the Johns Hopkins ADRC Autopsy Cohort (JHAAC). The JHAAC includes brain tissue from a substantial number of subjects who were cognitively normal shortly before death, but were found to have substantial AD pathology on autopsy, referred to as 'asymptomatic AD'. The JHAAC also includes brain tissue from controls, subjects with MCI and patients with AD. We will examine three hypotheses in this project.
Aim 1 : We will test the hypothesis that amyloid-beta (AP) oligomers, not AB deposits, are responsible for cognitive decline. We will determine whether AP40, AP42 and AB oligomers distinguish the cognitive phenotypes of subjects with similar levels of AD pathology, as measured by the standard Braak and CERAD scales. In addition, we will examine whether the significant AB 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 AB in vivo.
Aim 2 : We will test the hypothesis that the process that couples AB deposition with neuronal/synaptic abnormalities is associated with Tau phosphorylation or cleavage. We propose to quantitate the amount of Tau phosphorylation and fragmentation in JHAAC 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 AB monomers, AB 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.
Understanding the biochemical mechanisms that underiie the accumulation of Alzheimer's pathology in the brains of some elderiy subjects (amyloid plaques and neurofibrillary tangles) and determining why some subjects with Alzheimer's pathology become demented and others remain cognitively normal is of crucial importance in developing strategies to combat Alzheimer's disease, a neurodegenerative disorder which affects over 6 million Americans.
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