Dean Hartley (12.5) presented data on the deleterious effects of "protofibrillar" Aβ on neurons. Several other groups have reported that amyloid protofibrils of one sort of another are toxic to neurons (e.g., Oda, Aksenova, Roher or Lambert). And Hartley and Selkoe have previously reported that 30-40 kD, 5-10 nanometer fibrils are toxic and can increase electrical activity of cultured neurons (J Neuroscience;19(20):8876-8884). Low-molecular weight amyloid peptide (e.g., non-fibrillar) does not alter the firing rate (normally 60 action potentials/min) in their preparations while protofibrillar amyloid increases the firing rate to 350 action potentials/min. If the protofibrils are washed out within 30 minutes, the increase in firing rate will return to baseline. The addition of protofibrillar amyloid (1 micro molar) with 100 micromolar D-APV (an NMDA antagonist) resulted in a partial block of the effect (69 action potentials/min) which was not further reduced by the addition of the competitive NMDA antagonists NBQX. The addition of higher molecular weight fibrils yielded similar results. However, with the higher molecular weight fibrils, additional activity was blocked by the NBQX. Following exposure of mouse neuroblastoma cells to protofibrils (15 micromolar for two days), they observed a significant loss of processes. In fetal progenitor cells, exposure for one hour caused a 70 percent reduction in primary processes and a 90 percent reduction in secondary processes. To determine if exposure to protofibrils induced apoptosis, they labeled exposed cells with Annexin-V, which binds to the phosphatidyl-serine present on the internal side of the plasma membrane. Under normal conditions, Annexin labeling should be negative, but if the membrane flips, as during apoptosis, labeling would be detected. They observed strong Annexin labeling on the cell body and in patches along specific processes (akin to Greg Cole's "synaptosis"). Further evidence that toxicity may be along an apoptotic pathway was the accumulation of caspase-3 within the exposed cells. While the detection of Annexin suggests a rapid activation by protofibrils, Hartley pointed out that the signal to noise ratio was such that at least 12 hours was necessary to see a strong enough signal in their system.—Brian Cummings


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