Alzheimer's Aβ assembly binds sodium pump and blocks endothelial NOS activity via ROS-PKC pathway in brain vascular endothelial cells
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Evaluation Summary:
This paper examines the effects of amylospheroids, highly neurotoxic assemblies of β-amyloid, on aortic function and on cultured cells. The authors propose that the interaction of amylospheroids with the sodium pump in endothelial cells induces production of reactive oxygen species to ultimately comprise nitric oxide generation. The study provides some new insight into mechanisms underlying brain blood vessel dysfunction and will be interesting neuroscientists who study neurovascular contribution to neurodegenerative diseases. The conclusions of the manuscript are supported by the data, but alternative approaches would make the study stronger.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Evaluation Summary:
This paper examines the effects of amylospheroids, highly neurotoxic assemblies of β-amyloid, on aortic function and on cultured cells. The authors propose that the interaction of amylospheroids with the sodium pump in endothelial cells induces production of reactive oxygen species to ultimately comprise nitric oxide generation. The study provides some new insight into mechanisms underlying brain blood vessel dysfunction and will be interesting neuroscientists who study neurovascular contribution to neurodegenerative diseases. The conclusions of the manuscript are supported by the data, but alternative approaches would make the study stronger.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the …
Evaluation Summary:
This paper examines the effects of amylospheroids, highly neurotoxic assemblies of β-amyloid, on aortic function and on cultured cells. The authors propose that the interaction of amylospheroids with the sodium pump in endothelial cells induces production of reactive oxygen species to ultimately comprise nitric oxide generation. The study provides some new insight into mechanisms underlying brain blood vessel dysfunction and will be interesting neuroscientists who study neurovascular contribution to neurodegenerative diseases. The conclusions of the manuscript are supported by the data, but alternative approaches would make the study stronger.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
In this manuscript, the authors use extensive pharmacologic manipulations to examine a pathway by which oligomeric amyloid beta assemblies bind to a sodium potassium pump subunit and lead to an increased proportion of inactive endothelial nitric oxide synthetase. They speculate that this reduced eNOS activity in endothelial cells could underlie changes in cerebral perfusion in Alzheimer's disease. While the idea that eNOS activity is altered in Alzheimer's is not novel, having been described elsewhere in relation to amyloid beta, the authors clearly outline a new pathway involving NAKalpha3 providing mechanistic insight into eNOS changes. Further, their data uses immunofluorescence, western blotting, and qPCR to show rat aorta and cultured human brain microvessel endothelial cells express NAKalpha3--a …
Reviewer #1 (Public Review):
In this manuscript, the authors use extensive pharmacologic manipulations to examine a pathway by which oligomeric amyloid beta assemblies bind to a sodium potassium pump subunit and lead to an increased proportion of inactive endothelial nitric oxide synthetase. They speculate that this reduced eNOS activity in endothelial cells could underlie changes in cerebral perfusion in Alzheimer's disease. While the idea that eNOS activity is altered in Alzheimer's is not novel, having been described elsewhere in relation to amyloid beta, the authors clearly outline a new pathway involving NAKalpha3 providing mechanistic insight into eNOS changes. Further, their data uses immunofluorescence, western blotting, and qPCR to show rat aorta and cultured human brain microvessel endothelial cells express NAKalpha3--a protein previously believed to be a neuron-specific.
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Reviewer #2 (Public Review):
The current study by Sasahara et al. examined the cerebrovascular effects of amylospheroids (ASPD), highly neurotoxic ~30-mer assemblies of β-amyloid (Aβ), which the author's group purified from human brains of AD patients and characterized in previous studies. The authors propose that the aberrant interaction of ASPD with NAKalpha3 in endothelial cells induces production of reactive oxygen species (ROS) from mitochondria and activates protein kinase C (PKC). In turn, PKC phosphorylates inactive form of eNOS, reduces NO production, and attenuates carbachol-induced vasorelaxation. These conclusions were based on ASPD immunostaining of brain sections from AD patients, the ASPD effects on carbachol (a muscarinic M3 receptor agonist)-induced vasorelaxation in rat aortic rings, and in vitro studies in primary …
Reviewer #2 (Public Review):
The current study by Sasahara et al. examined the cerebrovascular effects of amylospheroids (ASPD), highly neurotoxic ~30-mer assemblies of β-amyloid (Aβ), which the author's group purified from human brains of AD patients and characterized in previous studies. The authors propose that the aberrant interaction of ASPD with NAKalpha3 in endothelial cells induces production of reactive oxygen species (ROS) from mitochondria and activates protein kinase C (PKC). In turn, PKC phosphorylates inactive form of eNOS, reduces NO production, and attenuates carbachol-induced vasorelaxation. These conclusions were based on ASPD immunostaining of brain sections from AD patients, the ASPD effects on carbachol (a muscarinic M3 receptor agonist)-induced vasorelaxation in rat aortic rings, and in vitro studies in primary human brain endothelial cells, including the effect of ASPD on carbachol-induced eNOS phosphorylation and NO production and ASPD-induced ROS production. These data add a new class of mechanisms by which Aβ impairs neurovascular regulation in the brain, and the manuscript could make an interesting contribution to the field of vascular contributions to cognitive impairment and dementia.
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