Tg2576 Cortical Neurons That Express Human Ab Are Susceptible To Extracellular A Beta-Induced, K+ Efflux Dependent Neurodegeneration

Background: One of the key pathological features of AD is the formation of insoluble amyloid plaques. The major constituent of these extracellular plaques is the beta-amyloid peptide (A beta), although A beta is also found to accumulate intraneuronally in AD. Due to the slowly progressive nature of the disease, it is likely that neurons are exposed to sublethal concentrations of both intracellular and extracellular A beta for extended periods of time.Results: In this study, we report that daily exposure to a sublethal concentration of A beta(1-40) (1 mu M) for six days induces substantial apoptosis of cortical neurons cultured from Tg2576 mice (which express substantial but sublethal levels of intracellular A beta). Notably, untreated Tg2576 neurons of similar age did not display any signs of apoptosis, indicating that the level of intracellular A beta present in these neurons was not the cause of toxicity. Furthermore, wildtype neurons did not become apoptotic under the same chronic A beta(1-40) treatment. We found that this apoptosis was linked to Tg2576 neurons being unable to maintain K+ homeostasis following A beta treatment. Furthermore, blocking K+ efflux protected Tg2576 neurons from A beta-induced neurotoxicity. Interestingly, chronic exposure to 1 mu M A beta 1-40 caused the generation of axonal swellings in Tg2576 neurons that contained dense concentrations of hyperphosphorylated tau. These were not observed in wildtype neurons under the same treatment conditions.Conclusions: Our data suggest that when neurons are chronically exposed to sublethal levels of both intra-and extracellular A beta, this causes a K+-dependent neurodegeneration that has pathological characteristics similar to AD.