hypothesis of Alzheimer's disease: ..
Twenty years of the Alzheimer’s disease amyloid hypothesis: ..
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.
the amyloid cascade hypothesis of Alzheimer disease ..
The amyloid-beta (Abeta) peptides 40 and 42 are believed to feature in the synaptic dysfunction and neuronal loss associated with Alzheimer's disease. One proposed mechanism for the synaptic loss is via the interaction between Abeta and cell surface neurotransmitters and receptors, which subsequently affect the cell signaling. Another hypothesis is that formation of calcium-permeable channels by Abeta oligomers on the membrane directly disrupts calcium homeostasis and triggers cell death. Both mechanisms are likely to involve peptide-membrane interaction where the amphipathic cell membrane provides an extensive surface for amyloid interactions and is the primarily cellular structure that Abeta comes into contact with. Most of our knowledge comes from experiments done at high Abeta concentration (~uM, as compared with the nM peptide concentrations in vivo) where peptide-peptide interactions in solution might bias the real peptide-membrane interaction. Using single molecule total internal reflection fluorescence microscopy, we observe single Abeta oligomers diffusing on the membrane at physiological concentration (~4nM). Using single molecule photobleaching and fluorescence intensity to assess the oligomers' sizes, we track individual peptide species as they diffuse in the membrane. Our studies reveal a mixture of freely diffusing and membrane-immobilized oligomers and show that the membrane accelerates Abeta dimer formation. A comparison of the membrane-bound oligomer species created by Abeta40 and Abeta42 yields information on how the two additional residues on Abeta42 affect the peptide-peptide and peptide-membrane interactions. These studies help further our understanding of the role of peptide-membrane interactions in the formation and growth of the amyloid-beta oligomers that may contribute to Alzheimer's pathology.