Alzheimer's disease (AD) is a slowly progressive disease, both histopathologically and clinically. Early symptoms include mild memory loss and cognitive impairment that progress very insidiously to severe dementia. Biochemical and structural studies suggest clinical symptomology may initially be due to synaptic dysfunction, followed by more profound neuronal changes, that may include neuritic dystrophy, synaptic loss, and/or frank cell death (Anderton et al.,1 998; Morris et. al. 1996). The fundamental mechanism underlying this progressive pathophysiology is thought to be an age-related accumulation of amyloid beta-protein (Abeta) fibrils, ultimately observed as mature amyloid plaques at autopsy. However, the focus on end-stage tissue has led to the assumption that fibrils per se underlie the progression of AD. Our working hypothesis is that low molecular weight Abeta (monomer/dimer) transitions to prefibrillar, oligomeric forms of Abeta that can initiate neuronal dysfunction and can directly and/or via further transition to higher molecular weight polymers (fibrils), trigger neuronal loss. In support of this, Abeta oligomers have been identified in the cerebrospinal fluid of AD patients, prefibrillar forms of Abeta cause synaptic dysfunction and neuronal death, and soluble Abeta levels in brain correlate relatively well with cognitive impairment. Furthermore, we recently published that a metastable oligomeric form of Abeta, protofibrils (PF), can acutely increase the electrical activity of cortical neurons and reproducibly induce neurotoxicity. In this proposal, we will extend our preliminary data by focusing on: 1) identification of early markers of neuronal dysfunction and injury induced by prefibrillar forms of Abeta, 2) antagonism of this injury byreceptor antagonists and 3) biological characterization of naturally generated stable Abeta oligomers in culture. Our model and data suggest that the preelinical and clinical progression of AD is driven, in part by early temporal changes occurring in Abeta species, not just frank Abeta fibril formation. Deciphering and blocking the biological activity of PF is anovel approach that should help in elucidating the role of early Abeta intermediates in AD and in designing rational therapeutic strategies to slow or block the progression of AD.
| Ye, Chianping; Walsh, Dominic M; Selkoe, Dennis J et al. (2004) Amyloid beta-protein induced electrophysiological changes are dependent on aggregation state: N-methyl-D-aspartate (NMDA) versus non-NMDA receptor/channel activation. Neurosci Lett 366:320-5 |
| Ye, Chian P; Selkoe, Dennis J; Hartley, Dean M (2003) Protofibrils of amyloid beta-protein inhibit specific K+ currents in neocortical cultures. Neurobiol Dis 13:177-90 |
