Exogenous ß-amyloid peptide interferes with GLUT4 localization in neurons.

Aging represents a major risk factor for numerous illnesses that are of increasing importance to society, including two of the most prevalent: diabetes and Alzheimer's disease. Studies have shown that diabetes is a risk factor for spontaneous Alzheimer's disease. While these studies suggest that diabetes can contribute to Alzheimer's disease, the implications of AD on diabetes are practically unexplored. The major mediator of the pathophysiological effects, the Aß42 peptide, has been shown to enter neurons and lead to an alteration of the intracellular distribution of the molecular motor myosin Vb. Myosin Vb functions in memory and learning by participating in the strengthening of the long-term potentiation (LTP) of synaptic transmissions. It has also been implicated in the translocation of the glucose transporter, GLUT4, to the plasma membrane in response to insulin, a process that is defective in diabetes. Here, the effect on GLUT4 upon entry of the Aß42 peptide into cultured chick retinal neurons was explored. The results suggest an alteration in distribution and a reduced level at the cell surface, as well as an increased colocalization with myosin Vb, which can partially explain the changes in glucose metabolism associated with AD. It is also shown that the presence of the Aß40 peptide inhibits the internalization of the Aß42 peptide in cultured cells. Together, the results provide additional targets for the development of therapeutics against the progression and effects of Alzheimer's disease.

ß-Amyloid peptide is internalized into chick retinal neurons and alters the distribution of myosin Vb.

The most common neurodegenerative disorder afflicting the aging human population is Alzheimer's disease (AD). A major hallmark of AD is dementia from a loss of neuronal function, attributed to the presence and accumulation of ß-amyloid (Aß) peptide into senile plaques. Preceding senile plaque formation, abnormalities in axons can be observed as changes in morphologies and intracellular trafficking. Recently, it has been recognized that Aß also accumulates within neurons and this intraneuronal Aß accumulation has been reported to be critical in the disruption of synapses and cognitive function. Here, we report on the internalization of a fluorescently labeled Aß peptide into cultured chick retinal neurons. The pattern of Aß distribution during the time course of incubation is reminiscent of the endocytic pathway. Furthermore, the distribution of the internalized Aß peptide converges with that of myosin Vb and both relocalize from the axon to cell body. These observations are consistent with the hypothesis that AD proceeds as a result of an imbalance between Aß production and Aß clearance, suggesting a role for myosin Vb in this process.

Amyloid-ß decreases nitric oxide production in cultured retinal neurons: a possible mechanism for synaptic dysfunction in Alzheimer's disease?

The neurotoxicity of the amyloid-ß peptide (Aß) appears to be, at least in part, related to pathological activation of glutamate receptors by Aß aggregates. However, the downstream signaling pathways leading to neurodegeneration are still incompletely understood. Hyperactivation of nitric oxide synthase (NOS) and increased nitric oxide (NO) production have been implicated in excitotoxic neuronal damage caused by overactivation of glutamate receptors, and it has been suggested that increased NO levels might also play a role in neurotoxicity in Alzheimer's disease. We have examined the effect of blockade of NO production on the neurotoxicity instigated by Aß42 and by elevated concentrations of glutamate in chick embryo retinal neurons in culture. Results showed that L-nitroarginine methyl ester, a potent inhibitor of all NOS isoforms, had no protective effect against neuronal death induced by either Aß42 (20 µM) or glutamate (1 mM). Surprisingly, at short incubation times both Aß and glutamate decreased NO production in retinal neuronal cultures in the absence of neuronal death. Thus, excitotoxic insults induced by Aß and glutamate cause inhibition rather than activation of NO synthase in retinal neurons, suggesting that cell death induced by Aß or glutamate is not related to increased NO production. On the other hand, considering the role of NO in long term potentiation and synaptic plasticity, the decrease in NO levels instigated by Aß and glutamate suggests a possible mechanism leading to synaptic failure in AD.