Sex-specific Mechanisms of Cerebral Microvascular BK Dysfunction in a Mouse Model of Alzheimer's Disease

Overview

Journal Alzheimers Dement

Specialties Neurology
Psychiatry

Date 2024 Dec 19

PMID 39698895

Authors

Josiane F Silva

Felipe D Polk

Paige E Martin

Stephenie H Thai

Andrea Savu

Matthew Gonzales

Allison M Kath

Michael T Gee

Paulo W Pires

Affiliations

Soon will be listed here.

Abstract

Introduction: Cerebrovascular dysfunction occurs in Alzheimer's disease (AD), impairing hemodynamic regulation. Large conductance Ca-activated K channels (BK) regulate cerebrovascular reactivity and are impaired in AD. BK activity depends on intracellular Ca (Ca sparks) and nitro-oxidative post-translational modifications. However, whether these mechanisms underlie BK impairment in AD remains unknown.

Methods: Cerebral arteries from 5x-FAD and wild-type (WT) littermates were used for molecular biology, electrophysiology, ex vivo, and in vivo experiments.

Results: Arterial BK activity is reduced in 5x-FAD via sex-dependent mechanisms: in males, there is lower BK subunit expression and less Ca sparks. In females, we observed reversible nitro-oxidative modification of BK. Further, BK is involved in hemodynamic regulation in WT mice, and its dysfunction is associated with vascular deficits in 5x-FAD.

Discussion: Our data highlight the central role played by BK in cerebral hemodynamic regulation and that molecular mechanisms of its impairment diverge based on sex in 5x-FAD.

Highlights: Cerebral microvascular BK dysfunction occurs in both female and male 5x-FAD. Reduction in BK subunit protein and Ca sparks drive the dysfunction in males. Nitro-oxidative stress is present in females, but not males, 5x-FAD. Reversible nitro-oxidation of BK underlies BK dysfunction in female 5x-FAD.

Citing Articles

Sex-specific mechanisms of cerebral microvascular BK dysfunction in a mouse model of Alzheimer's disease.

Silva J, Polk F, Martin P, Thai S, Savu A, Gonzales M Alzheimers Dement. 2024; 21(2):e14438.

PMID: 39698895 PMC: 11848394. DOI: 10.1002/alz.14438.

References

Handy D, Loscalzo J . Nitric oxide and posttranslational modification of the vascular proteome: S-nitrosation of reactive thiols. Arterioscler Thromb Vasc Biol. 2006; 26(6):1207-14. DOI: 10.1161/01.ATV.0000217632.98717.a0. View

Jellinger K . Alzheimer disease and cerebrovascular pathology: an update. J Neural Transm (Vienna). 2002; 109(5-6):813-36. DOI: 10.1007/s007020200068. View

Schubert R, Nelson M . Protein kinases: tuners of the BKCa channel in smooth muscle. Trends Pharmacol Sci. 2001; 22(10):505-12. DOI: 10.1016/s0165-6147(00)01775-2. View

Balu D, Valencia-Olvera A, Deshpande A, Narayanam S, Konasani S, Pattisapu S . Estradiol improves behavior in FAD transgenic mice that express but not after ovariectomy. Front Endocrinol (Lausanne). 2024; 15:1374825. PMC: 11089251. DOI: 10.3389/fendo.2024.1374825. View

Jackson W . Myogenic Tone in Peripheral Resistance Arteries and Arterioles: The Pressure Is On!. Front Physiol. 2021; 12:699517. PMC: 8339585. DOI: 10.3389/fphys.2021.699517. View

Venema R, Sayegh H, Kent J, Harrison D . Identification, characterization, and comparison of the calmodulin-binding domains of the endothelial and inducible nitric oxide synthases. J Biol Chem. 1996; 271(11):6435-40. DOI: 10.1074/jbc.271.11.6435. View

Thuringer D, Findlay I . Contrasting effects of intracellular redox couples on the regulation of maxi-K channels in isolated myocytes from rabbit pulmonary artery. J Physiol. 1997; 500 ( Pt 3):583-92. PMC: 1159410. DOI: 10.1113/jphysiol.1997.sp022044. View

Pritchard H, Pires P, Yamasaki E, Thakore P, Earley S . Nanoscale remodeling of ryanodine receptor cluster size underlies cerebral microvascular dysfunction in Duchenne muscular dystrophy. Proc Natl Acad Sci U S A. 2018; 115(41):E9745-E9752. PMC: 6187127. DOI: 10.1073/pnas.1804593115. View

Reed J, Pareek T, Sriramula S, Pabbidi M . Aging influences cerebrovascular myogenic reactivity and BK channel function in a sex-specific manner. Cardiovasc Res. 2019; 116(7):1372-1385. DOI: 10.1093/cvr/cvz314. View

10.

Grimm P, Sansom S . BK channels and a new form of hypertension. Kidney Int. 2010; 78(10):956-62. PMC: 3134256. DOI: 10.1038/ki.2010.272. View

11.

Furuta S . Basal S-Nitrosylation Is the Guardian of Tissue Homeostasis. Trends Cancer. 2017; 3(11):744-748. DOI: 10.1016/j.trecan.2017.09.003. View

12.

Toro C, Zhang L, Cao J, Cai D . Sex differences in Alzheimer's disease: Understanding the molecular impact. Brain Res. 2019; 1719:194-207. PMC: 6750802. DOI: 10.1016/j.brainres.2019.05.031. View

13.

Blackwell J, Silva J, Louis E, Savu A, Largent-Milnes T, Brooks H . Cerebral arteriolar and neurovascular dysfunction after chemically induced menopause in mice. Am J Physiol Heart Circ Physiol. 2022; 323(5):H845-H860. PMC: 9602916. DOI: 10.1152/ajpheart.00276.2022. View

14.

Nelson M, Ledoux J, Taylor M, Bonev A, Hannah R, Solodushko V . Spinning Disk Confocal Microscopy of Calcium Signalling in Blood Vessel Walls. Microsc Anal (Am Ed). 2012; 24(2):5-8. PMC: 3324844. View

15.

Bryant A, Li Z, Jayakumar R, Serrano-Pozo A, Woost B, Hu M . Endothelial Cells Are Heterogeneous in Different Brain Regions and Are Dramatically Altered in Alzheimer's Disease. J Neurosci. 2023; 43(24):4541-4557. PMC: 10278684. DOI: 10.1523/JNEUROSCI.0237-23.2023. View

16.

Cheng Y, Lin C, Lane H . From Menopause to Neurodegeneration-Molecular Basis and Potential Therapy. Int J Mol Sci. 2021; 22(16). PMC: 8395405. DOI: 10.3390/ijms22168654. View

17.

Silva J, Polk F, Martin P, Thai S, Savu A, Gonzales M . Sex-specific mechanisms of cerebral microvascular BK dysfunction in a mouse model of Alzheimer's disease. Alzheimers Dement. 2024; 21(2):e14438. PMC: 11848394. DOI: 10.1002/alz.14438. View

18.

Pautz A, Art J, Hahn S, Nowag S, Voss C, Kleinert H . Regulation of the expression of inducible nitric oxide synthase. Nitric Oxide. 2010; 23(2):75-93. DOI: 10.1016/j.niox.2010.04.007. View

19.

Taylor J, Pritchard H, Walsh K, Strangward P, White C, Hill-Eubanks D . Functionally linked potassium channel activity in cerebral endothelial and smooth muscle cells is compromised in Alzheimer's disease. Proc Natl Acad Sci U S A. 2022; 119(26):e2204581119. PMC: 9245656. DOI: 10.1073/pnas.2204581119. View

20.

Kyle B, Braun A . The regulation of BK channel activity by pre- and post-translational modifications. Front Physiol. 2014; 5:316. PMC: 4141542. DOI: 10.3389/fphys.2014.00316. View