Alzheimer’s Aβ assembly binds sodium pump and blocks endothelial NOS activity via ROS-PKC pathway

AbstractAmyloid β-protein (Aβ) may contribute to worsening of Alzheimer’s disease (AD) through vascular dysfunction, but the actual molecular mechanisms remain controversial. Using ex-vivo blood vessels and primary endothelial cells derived from human brain microvessels, we revealed that patient-derived Aβ assemblies, termed amylospheroids (ASPD), exist on the microvascular surface in patient brains and inhibit vasorelaxation through binding to the α3 subunit of sodium, potassium-ATPase (NAKα3) on endothelial cells. Interestingly, NAKα3 also serves as the toxic target of ASPD in neurons. ASPD elicit neurodegeneration through calcium overload, while ASPD suppress vasorelaxation by inhibiting nitric oxide (NO) production. ASPD-NAKα3 interaction on cerebrovascular endothelial cells disturbs the NO release by inactivating endothelial NO synthase through mitochondrial reactive oxygen species and protein kinase C. The findings suggest that ASPD may dually contribute to neuronal and vascular pathologies through binding to NAKα3. Thus, blocking the ASPD-NAKα3 interaction may be a useful target for AD therapy.

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Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1421182112 ◽

2015 ◽

Vol 112 (32) ◽

pp. E4465-E4474 ◽

Cited By ~ 67

Author(s):

Takayuki Ohnishi ◽

Masako Yanazawa ◽

Tomoya Sasahara ◽

Yasuki Kitamura ◽

Hidekazu Hiroaki ◽

...

Keyword(s):

Specific Activity ◽

Amyloid Β ◽

Amyloid Β Protein ◽

Aβ Oligomers ◽

Alzheimer Patient ◽

Knowledge Based ◽

Β Protein ◽

Mature Neurons ◽

Α3 Subunit ◽

Target Binding

Neurodegeneration correlates with Alzheimer’s disease (AD) symptoms, but the molecular identities of pathogenic amyloid β-protein (Aβ) oligomers and their targets, leading to neurodegeneration, remain unclear. Amylospheroids (ASPD) are AD patient-derived 10- to 15-nm spherical Aβ oligomers that cause selective degeneration of mature neurons. Here, we show that the ASPD target is neuron-specific Na+/K+-ATPase α3 subunit (NAKα3). ASPD-binding to NAKα3 impaired NAKα3-specific activity, activated N-type voltage-gated calcium channels, and caused mitochondrial calcium dyshomeostasis, tau abnormalities, and neurodegeneration. NMR and molecular modeling studies suggested that spherical ASPD contain N-terminal-Aβ–derived “thorns” responsible for target binding, which are distinct from low molecular-weight oligomers and dodecamers. The fourth extracellular loop (Ex4) region of NAKα3 encompassing Asn879 and Trp880 is essential for ASPD–NAKα3 interaction, because tetrapeptides mimicking this Ex4 region bound to the ASPD surface and blocked ASPD neurotoxicity. Our findings open up new possibilities for knowledge-based design of peptidomimetics that inhibit neurodegeneration in AD by blocking aberrant ASPD–NAKα3 interaction.

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Amyloid β-protein precursor and apolipoprotein E production in cultured cerebral endothelial cells isolated from brains of patients with neurodegenerative disorders at autopsy

Amyloid ◽

10.3109/13506129508999004 ◽

1995 ◽

Vol 2 (4) ◽

pp. 229-233 ◽

Cited By ~ 5

Author(s):

John M. Wells ◽

Anil Amaratunga ◽

Daniel C. McKenna ◽

Carmela R. Abraham ◽

Richard E. Fine

Keyword(s):

Endothelial Cells ◽

Apolipoprotein E ◽

Neurodegenerative Disorders ◽

Amyloid Β ◽

Amyloid Β Protein ◽

Protein Precursor ◽

Cerebral Endothelial Cells ◽

Β Protein

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Von Willebrand factor promoter targets the expression of amyloid β protein precursor to brain vascular endothelial cells of transgenic mice

Journal of Alzheimer s Disease ◽

10.3233/jad-2003-5209 ◽

2003 ◽

Vol 5 (2) ◽

pp. 149-158 ◽

Cited By ~ 5

Author(s):

Nadia Jahroudi ◽

Alvin Schmaier ◽

Sujata Srikanth ◽

Fakhri Mahdi ◽

Frances A. Lutka ◽

...

Keyword(s):

Endothelial Cells ◽

Transgenic Mice ◽

Vascular Endothelial Cells ◽

Amyloid Β ◽

Amyloid Β Protein ◽

Vascular Endothelial ◽

Protein Precursor ◽

Β Protein ◽

Von Willebrand ◽

Willebrand Factor

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Molecular mechanisms of resveratrol and EGCG in inhibition of Aβ42 aggregation and disruption of Aβ42 protofibril: similarities and differences

Physical Chemistry Chemical Physics ◽

10.1039/d1cp01913a ◽

2021 ◽

Author(s):

Fangying Li ◽

Chendi Zhan ◽

Xuewei Dong ◽

Guanghong Wei

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Amyloid Β ◽

Amyloid Β Protein ◽

Β Protein ◽

Aβ Aggregation ◽

Similarities And Differences ◽

Aβ Fibrils

The aggregation of amyloid-β protein (Aβ) into fibrillary deposits is implicated in Alzheimer's disease (AD), and inhibiting Aβ aggregation and clearing Aβ fibrils are considered as promising strategies to treat...

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The Inhalation Anesthetic Isoflurane Induces a Vicious Cycle of Apoptosis and Amyloid β-Protein Accumulation

Yearbook of Anesthesiology and Pain Management ◽

10.1016/s1073-5437(08)70801-5 ◽

2008 ◽

Vol 2008 ◽

pp. 35-36

Author(s):

H.T. Lee

Keyword(s):

Amyloid Β ◽

Protein Accumulation ◽

Amyloid Β Protein ◽

Vicious Cycle ◽

Inhalation Anesthetic ◽

Β Protein

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LOW-DOSE PHOSPHODIESTERASE III INHIBITOR (CILOSTAZOL) REDUCES THE VASCULAR AMYLOID BURDEN IN AMYLOID-Β PROTEIN PRECURSOR TRANSGENIC MICE

10.26226/morressier.58e389aed462b802923858c2 ◽

2017 ◽

Author(s):

Yusuke Yakushiji

Keyword(s):

Transgenic Mice ◽

Low Dose ◽

Amyloid Β ◽

Amyloid Β Protein ◽

Amyloid Burden ◽

Protein Precursor ◽

Β Protein ◽

Phosphodiesterase Iii Inhibitor ◽

Phosphodiesterase Iii

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Extracellular Protein Aggregates Colocalization and Neuronal Dystrophy in Comorbid Alzheimer’s and Creutzfeldt–Jakob Disease: A Micromorphological Pilot Study on 20 Brains

International Journal of Molecular Sciences ◽

10.3390/ijms22042099 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2099

Author(s):

Nikol Jankovska ◽

Tomas Olejar ◽

Radoslav Matej

Keyword(s):

Prion Protein ◽

Fluorescent Microscopy ◽

Amyloid Β ◽

Amyloid Β Protein ◽

Β Protein ◽

Key Characteristics ◽

Jakob Disease ◽

Immunohistochemical Methods ◽

Confocal Fluorescent Microscopy ◽

Codon 129

Alzheimer’s disease (AD) and sporadic Creutzfeldt–Jakob disease (sCJD) are both characterized by extracellular pathologically conformed aggregates of amyloid proteins—amyloid β-protein (Aβ) and prion protein (PrPSc), respectively. To investigate the potential morphological colocalization of Aβ and PrPSc aggregates, we examined the hippocampal regions (archicortex and neocortex) of 20 subjects with confirmed comorbid AD and sCJD using neurohistopathological analyses, immunohistochemical methods, and confocal fluorescent microscopy. Our data showed that extracellular Aβ and PrPSc aggregates tended to be, in most cases, located separately, and “compound” plaques were relatively rare. We observed PrPSc plaque-like structures in the periphery of the non-compact parts of Aβ plaques, as well as in tau protein-positive dystrophic structures. The AD ABC score according to the NIA-Alzheimer’s association guidelines, and prion protein subtype with codon 129 methionine–valine (M/V) polymorphisms in sCJD, while representing key characteristics of these diseases, did not correlate with the morphology of the Aβ/PrPSc co-aggregates. However, our data showed that PrPSc aggregation could dominate during co-aggregation with non-compact Aβ in the periphery of Aβ plaques.

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