Cerebral accumulation of amyloid β-protein (Aβ) is generally believed to play a critical role in the pathogenesis of Alzheimer's disease (AD). Recent evidence suggests that Aβ-induced synaptic dysfunction is one of earliest pathogenic events observed in AD. Here we report that synthetic Aβ1-42 strongly inhibited the induction of long-term potentiation (LTP) in the CA1 region of rat hippocampal slices. To ascertain which Aβ1-42 sequences contribute to the impairment of LTP, we compared actions of several Aβ fragments and found that the sequence within 25-35 region of Aβ mainly contributes to the expression of LTP impairment. Importantly, we show that insulin and insulin-like growth factor-1 significantly inhibit Aβ oligomer formation, particularly dimers and trimers, and ameliorate the synthetic Aβ-induced suppression of LTP. Furthermore, dithiothreitol was found to be capable of significantly preventing the inhibitory effect of insulin on Aβ oligomer formation. In contrast, hemoglobin promotes Aβ oligomer formation and enhances Aβ-mediated inhibition of LTP induction. These results suggest that insulin may have utility in treating the earliest stages of Aβ-induced synaptic dysfunction in AD patients.
|Number of pages||11|
|Journal||Neurobiology of Aging|
|Publication status||Published - 2009 Mar|
All Science Journal Classification (ASJC) codes
- Clinical Neurology
- Developmental Biology
- Geriatrics and Gerontology