Year: 2025
Type: article
Abstract: A hallmark of Alzheimer's disease is reduced cerebral blood flow, which appears to occur early in disease progression and has been associated with amyloid β (Aβ) accumulation. Cerebral artery diameter is regulated by calcium influx via voltage‐gated L‐type Ca V 1.2 channels, which contribute to arterial myocyte contractility. The potential effects of Aβ on vascular Ca V 1.2 channels remain unclear. To address this knowledge gap, we test the hypothesis that Aβ alters vascular Ca V 1.2 channel spatiotemporal properties. Using freshly dissected cerebral arteries and arterial myocytes from wild‐type (WT) mice, super‐resolution imaging revealed that Aβ 1‐42 , but not Aβ 1‐40 , increased the clustering of Ca V 1.2 channels in male but not female or ovariectomized female arterial myocytes. This Aβ 1‐42 ‐associated Ca V 1.2 clustering appears to depend on NADPH oxidases, protein kinase C and protein kinase A signalling. Studies using male arterial myocytes from S1928A knockin mice suggested that Aβ 1‐42 effects on Ca V 1.2 clustering require phosphorylation of the α1 C /Ca V 1.2 pore‐forming subunit at serine‐1928. Single‐channel electrophysiology showed increased Ca V 1.2 channel activity and cooperative gating in WT male arterial myocytes exposed to Aβ 1‐42 , but not in female WT or male S1928A myocytes. In functional studies, WT, but not S1928A, cerebral arteries acutely incubated with Aβ 1‐42 demonstrated enhanced constriction in response to the Ca V 1.2 channel agonist BayK8644. These findings provide insight into mechanisms by which Aβ may influence Ca V 1.2 properties and vascular contractility, potentially contributing to vascular changes in Alzheimer's disease. image Key points Specific amyloid‐β peptide (Aβ 1‐42 ) induces α1 C /Ca V 1.2 super‐clustering in cerebral vascular smooth muscle, enhancing Ca V 1.2 activity. Aβ 1‐42 engages distinct pathways involving NOX‐derived ROS‐activated PKC and PKA (through unknown mechanisms) to drive α1 C /Ca V 1.2 spatiotemporal reorganization leading to enhance cerebral artery contractile responses to Ca V 1.2 agonists. The Aβ 1‐42 ‐mediated PKC‐ and PKA‐dependent effects on α1 C /Ca V 1.2 spatiotemporal remodelling and cerebral artery contractility require phosphorylation of α1 C at S1928, as the effects are lost in S1928A tissue/cells. The molecular and functional changes occur exclusively in male vascular smooth muscle cells, revealing sex‐specific vulnerabilities in amyloid β‐related cerebrovascular pathology that are independent of sex hormones and establishing a potential mechanism for vascular dysfunction in conditions with elevated Aβ 1‐42 .
Source: The Journal of Physiology
DOI: 10.1113/jp289276
Authors: Jade L. Taylor, Miguel Martin‐Aragon Baudel, Eric Pereira da Silva, Johannes W. Hell, Madeline Nieves‐Cintron, Manuel F. Navedo
Institution: University of California, Davis
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,400
Awards: Coupling of vascular CaV1.2 channels in health and disease, G3119125940, G3588291844, G4302205960, G487464006, A single amino acid in CaV1.2 controls channel activity and arterial tone in hypertension, G518097869, G7586746257, Postsynaptic Signaling by Norepinephrine and cAMP, Pressure Regulation of Vascular CaV1.2 Channels
OpenAlex ID: W4417534671