Amyloid-β Decreases Nitric Oxide Production in Cultured Retinal Neurons: A Possible Mechanism for Synaptic Dysfunction in Alzheimer’s Disease?

Abstract

The neurotoxicity of the amyloid-β peptide (Aβ) appears to be, at least in part, related to pathological activation of glutamate receptors by Aβ 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 Aβ₄₂ 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 Aβ₄₂ (20 μM) or glutamate (1 mM). Surprisingly, at short incubation times both Aβ and glutamate decreased NO production in retinal neuronal cultures in the absence of neuronal death. Thus, excitotoxic insults induced by Aβ and glutamate cause inhibition rather than activation of NO synthase in retinal neurons, suggesting that cell death induced by Aβ 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 Aβ and glutamate suggests a possible mechanism leading to synaptic failure in AD.

Evaluation of retinal nerve fiber layer thickness in Alzheimer disease usingspectral-domain optical coherence tomography

“…The reason for the reduction of RNFL thickness in AD is likely the death of retinal ganglion cell axons in addition to retrograde degeneration resulting from loss of cortical neurons (6). The defects detected by OCT in a patient group with mild symptoms further supports that these defects may be specific to AD.…”

Alzheimer’s Disease: A Heme–Aβ Perspective

“…41,42 Decreased levels of NO have been observed in cultured neurons in the presence of Aβ. 43 It has been observed that NO plays a protective role against Aβ induced neuronal cell death, cerebrovascular dysfunction, and cerebral amyloid angiopathy. 44 Thus, decreased levels of NO may contribute to synaptic failure, which leads to memory impairment and neuronal cell death observed in AD.…”

Retinal Vascular Dysfunction Relates to Cognitive Impairment in Alzheimer Disease

“…[7][8][9] The finding of a significant correlation between the abnormal retinal arterial reaction to flickering light and the level of cognitive impairment in our AD patients suggests that microvascular dysfunction may be a component of AD pathophysiology. The cause of this microvascular dysfunction can only be hypothesized at this point but could theoretically relate to either disturbed neurovascular coupling mechanisms, increased vascular stiffness, or altered nitric oxide, factors that have been already shown to play a role in AD.…”