Amyloid-β disrupts unitary calcium entry through endothelial NMDA receptors in mouse cerebral arteries

2021 ◽  
pp. 0271678X2110395
Author(s):  
Emily C Peters ◽  
Michael T Gee ◽  
Lukas N Pawlowski ◽  
Allison M Kath ◽  
Felipe D Polk ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cerebral Arteries ◽  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Wild Type ◽  
Pial Arteries ◽  
Aspartate Receptor ◽  
Model Of Alzheimer’S Disease ◽  
Intracellular Ca ◽  
Cerebral Amyloid

Transient increases in intracellular Ca2+ activate endothelium-dependent vasodilatory pathways. This process is impaired in cerebral amyloid angiopathy, where amyloid- β(1-40) accumulates around blood vessels. In neurons, amyloid- β impairs the Ca2+-permeable N-methyl-D-aspartate receptor (NMDAR), a mediator of endothelium-dependent dilation in arteries. We hypothesized that amyloid- β(1-40) reduces NMDAR-elicited Ca2+ signals in mouse cerebral artery endothelial cells, blunting dilation. Cerebral arteries isolated from 4-5 months-old, male and female cdh5:Gcamp8 mice were used for imaging of unitary Ca2+ influx through NMDAR ( NMDAR sparklets) and intracellular Ca2+ transients. The NMDAR agonist NMDA (10 µmol/L) increased frequency of NMDAR sparklets and intracellular Ca2+ transients in endothelial cells; these effects were prevented by NMDAR antagonists D-AP5 and MK-801. Next, we tested if amyloid- β(1-40) impairs NMDAR-elicited Ca2+ transients. Cerebral arteries incubated with amyloid- β(1-40) (5 µmol/L) exhibited reduced NMDAR sparklets and intracellular Ca2+ transients. Lastly, we observed that NMDA-induced dilation of pial arteries is reduced by acute intraluminal amyloid- β(1-40), as well as in a mouse model of Alzheimer’s disease, the 5x-FAD, linked to downregulation of Grin1 mRNA compared to wild-type littermates. These data suggest that endothelial NMDAR mediate dilation via Ca2+-dependent pathways, a process disrupted by amyloid- β(1-40) and impaired in 5x-FAD mice.

Abstract P741: Elemental Calcium Influx Through Endothelial N-Methyl-D-Aspartate Receptors is Impaired by Acute Amyloid- β (1-40) in Cerebral Arteries

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Emily C Peters ◽  
Allison M Kath ◽  
Michael T Gee ◽  
Paulo W Pires
Keyword(s):  
Calcium Influx ◽  
Cerebral Arteries ◽  
Amyloid Β ◽  
Cyclopiazonic Acid ◽  
Time Lapse ◽  
Amyloid Angiopathy ◽  
Wild Type ◽  
Pial Arteries ◽  
Intracellular Ca ◽  
Nmdar Activation

Introduction: Cerebral amyloid angiopathy (CAA), the accumulation of amyloid- β (1-40) (A β ) around cerebral arteries, impairs endothelial function. Endothelium-dependent dilation is a consequence of transient increases in intracellular [Ca 2+ ] in endothelial cells (EC). The Ca 2+ permeable N-methyl-D-aspartate receptor (NMDAR) mediates endothelium-dependent dilation, although if these effects are dependent on Ca 2+ influx and transients, or if they are impaired by A β , remains undetermined. Hypothesis: A β inhibits endothelial NMDAR-mediated Ca 2+ influx and transients in murine pial arteries. Methods: We performed Ca 2+ time-lapse imaging of en face pial arteries from cdh5-GCaMP8 mice to quantify EC Ca 2+ events induced by NMDAR activation. Data are means ± SEM. Results: Elemental Ca 2+ entry through NMDAR, hereon called NMDAR sparklets , was assessed in arteries incubated with EGTA-AM and cyclopiazonic acid (CPA) to inhibit intracellular Ca 2+ transients. NMDA (10 μM) induced an increase in NMDAR sparklets frequency when compared to vehicle, an effect inhibited by the NMDAR antagonist D-APV (in Hz: 0.12±0.01 vs 0.44±0.05 vs 0.21±0.02, vehicle vs NMDA vs NMDA+D-APV, p<0.05). Further, pial arteries exposed to NMDA without EGTA-AM and CPA showed an increase in the frequency of intracellular Ca 2+ transients, also blocked by D-APV (in Hz: 0.24±0.05 vs 0.53±0.10 vs 0.28±0.05, vehicle vs NMDA vs NMDA+D-APV, p<0.05). We then tested the effects of A β on Ca 2+ events in pial artery EC. We observed that 30 minutes exposure to A β (5 μM) caused a significant reduction in NMDAR sparklets (in Hz: 0.62±0.07 vs 0.22±0.03, NMDA vs NMDA + A β , p<0.05) but did not significantly alter intracellular Ca 2+ transients (in Hz: 0.62±0.37 vs 0.27±0.07, NMDA vs NMDA + A β ). Lastly, we performed pressure myography on pial arteries of wild-type and 5x-FAD mice, a model of familial Alzheimer’s disease with rapid amyloid accumulation. 5x-FAD mice displayed impaired vasodilation to NMDA (vasodilation (%): 9.86±0.64 vs 4.22±2.76, wild-type vs 5x-FAD , p<0.05). Conclusion: These preliminary data suggest that A β impairs endothelial NMDAR-associated Ca 2+ influx events in cerebral arteries, which can impair blood flow in CAA patients, thus contributing to cognitive impairment.

scholarly journals Endothelial expression of human APP leads to cerebral amyloid angiopathy in mice

2020 ◽  
Author(s):  
Yuriko Tachida ◽  
Saori Miura ◽  
Rie Imamaki ◽  
Naomi Ogasawara ◽  
Hiroyuki Takuwa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessels ◽  
Cerebral Amyloid Angiopathy ◽  
Amyloid Β ◽  
Blood Levels ◽  
Amyloid Angiopathy ◽  
Disease Mechanisms ◽  
Age Dependent ◽  
Cerebral Amyloid ◽  
The Brain

AbstractThe deposition of amyloid β (Aβ) in blood vessels of the brain, known as cerebral amyloid angiopathy (CAA), is observed in more than 90% of Alzheimer’s disease (AD) patients. The presence of such CAA pathology is not as evident, however, in most mouse models of AD, thereby making it difficult to examine the contribution of CAA to the pathogenesis of AD. Since blood levels of soluble amyloid precursor protein (sAPP) in rodents are less than 1% of those in humans, we hypothesized that endothelial APP expression would be markedly lower in rodents, thus providing a reason for the poorly expressed CAA pathology. Here we generated mice that specifically express human APP770 in endothelial cells. These mice exhibited an age-dependent robust deposition of Aβ in brain blood vessels but not in the parenchyma. Crossing these animals with APP knock-in mice led to an expanded CAA pathology as evidenced by increased amounts of amyloid accumulated in the cortical blood vessels. These results show that both neuronal and endothelial APP contribute cooperatively to vascular Aβ deposition, and suggest that this mouse model will be useful for studying disease mechanisms underlying CAA and for developing novel AD therapeutics.

Abstract 211: The Role of Vascular Amyloid β in the Formation of Microhemorrhages in Cerebral Amyloid Angiopathy

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Susanne J van Veluw ◽  
Andreas Charidimou ◽  
Anand Viswanathan ◽  
Matthew Frosch ◽  
Brian Bacskai ◽  
...  
Keyword(s):  
Cerebral Amyloid Angiopathy ◽  
Amyloid Β ◽  
Direct Consequence ◽  
Transgenic Animals ◽  
Diagnostic Feature ◽  
Amyloid Angiopathy ◽  
Wild Type ◽  
Cerebral Amyloid

Introduction: Cerebral microhemorrhages are a key diagnostic feature of advanced cerebral amyloid angiopathy (CAA), but the underlying mechanisms remain poorly understood. We investigate the role of vascular Amyloid β (Aβ) in the formation of microhemorrhages in CAA, examining both human tissue and mouse models. Methods: First, we examined the histopathology of microhemorrhages, targeted with post-mortem MRI in humans. Brain slabs from nine cases with moderate/severe CAA were subjected to 7 T MRI. Samples were taken from representative MRI-observed microhemorrhages. On the corresponding histopathological sections we assessed the presence of Aβ in the walls of involved vessels, as well as number of Aβ-positive cortical vessels in areas (<2 mm) surrounding the rupture site. Second, to evaluate microhemorrhage formation in real-time in 3D, we performed in vivo two-photon microscopy in aged APP/PS1 mice with advanced CAA. Mice with previously installed cranial windows were injected with fluorescently labeled anti-fibrin, dextran, and methoxy-XO4 to study clot formation (i.e. microhemorrhages) and their spatial localization in relation to Aβ-positive vessels. Results: Human data: in 7/19 microhemorrhages the involved vessels were preserved. Only one of these vessels was positive for Aβ. Moreover, the density of Aβ-positive cortical vessels was lower close to the site of microhemorrhage (~1 positive vessel/mm 2 ), compared to control areas (~2 positive vessels/mm 2 ). Mouse data: we studied six transgenic ~21 month old APP/PS1 mice and two age-matched wild-type littermates. Mean number of in vivo observed microhemorrhages did not differ between groups (Tg: 1.3 / WT: 1), but the transgenic mice tended to have bigger microhemorrhages (mean size 4706 μm 3 ) than their wild-type controls (2505 μm 3 ). Interestingly, in the transgenic animals only one microhemorrhage was found in close proximity to vascular Aβ deposits. Conclusions: These findings question the widely held assumption that microhemorrhages in CAA are a direct consequence of Aβ deposition in the walls of responsible vessels. Our observations suggest that microhemorrhage formation may not be a direct consequence of more severe CAA locally, but may occur preferentially in areas of relatively low CAA.

scholarly journals Cerebral amyloid angiopathy severity is linked to dilation of juxtacortical perivascular spaces

2015 ◽  
Vol 36 (3) ◽  
pp. 576-580 ◽  
Author(s):  
Susanne J van Veluw ◽  
Geert Jan Biessels ◽  
Willem H Bouvy ◽  
Wim GM Spliet ◽  
Jaco JM Zwanenburg ◽  
...  
Keyword(s):  
Cerebral Amyloid Angiopathy ◽  
Small Vessel Disease ◽  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Perivascular Spaces ◽  
Resonance Imaging ◽  
Centrum Semiovale ◽  
Tissue Sections ◽  
Cortical Areas ◽  
Cerebral Amyloid

Perivascular spaces are an emerging marker of small vessel disease. Perivascular spaces in the centrum semiovale have been associated with cerebral amyloid angiopathy. However, a direct topographical relationship between dilated perivascular spaces and cerebral amyloid angiopathy severity has not been established. We examined this association using post-mortem magnetic resonance imaging in five cases with evidence of cerebral amyloid angiopathy pathology. Juxtacortical perivascular spaces dilation was evaluated on T2 images and related to cerebral amyloid angiopathy severity in overlying cortical areas on 34 tissue sections stained for Amyloid β. Degree of perivascular spaces dilation was significantly associated with cerebral amyloid angiopathy severity (odds ratio = 3.3, 95% confidence interval 1.3–7.9, p = 0.011). Thus, dilated juxtacortical perivascular spaces are a promising neuroimaging marker of cerebral amyloid angiopathy severity.

scholarly journals A fragment of cell adhesion molecule L1 reduces amyloid-β plaques in a mouse model of Alzheimer’s disease

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Junkai Hu ◽  
Stanley Li Lin ◽  
Melitta Schachner
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Transforming Growth Factor ◽  
Amyloid Β ◽  
Wild Type ◽  
Model Of Alzheimer’S Disease ◽  
Cell Adhesion Molecule L1

AbstractDeposition of amyloid-β (Aβ) in the brain is one of the important histopathological features of Alzheimer’s disease (AD). Previously, we reported a correlation between cell adhesion molecule L1 (L1) expression and the occurrence of AD, but its relationship was unclear. Here, we report that the expression of L1 and a 70 kDa cleavage product of L1 (L1-70) was reduced in the hippocampus of AD (APPswe) mice. Interestingly, upregulation of L1-70 expression in the hippocampus of 18-month-old APPswe mice, by parabiosis involving the joining of the circulatory system of an 18-month-old APPswe mouse with a 2-month-old wild-type C57BL/6 mouse, reduced amyloid plaque deposition. Furthermore, the reduction was accompanied by the appearance of a high number of activated microglia. Mechanistically, we observed that L1-70 could combine with topoisomerase 1 (Top1) to form a complex, L1-70/Top1, that was able to regulate expression of macrophage migration inhibitory factor (MIF), resulting in the activation of microglia and reduction of Aβ plaques. Also, transforming growth factor β1 (TGFβ-1) transferred from the blood of young wild-type C57BL/6 mice to the aged AD mice, was identified as a circulating factor that induces full-length L1 and L1-70 expression. All together, these findings suggest that L1-70 contributes to the clearance of Aβ in AD, thereby adding a novel perspective in understanding AD pathogenesis.

scholarly journals Evidence of amyloid-β cerebral amyloid angiopathy transmission through neurosurgery

2018 ◽  
Vol 135 (5) ◽  
pp. 671-679 ◽  
Author(s):  
Zane Jaunmuktane ◽  
Annelies Quaegebeur ◽  
Ricardo Taipa ◽  
Miguel Viana-Baptista ◽  
Raquel Barbosa ◽  
...  
Keyword(s):  
Cerebral Amyloid Angiopathy ◽  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Cerebral Amyloid

Vessels Sing Their ARIAs: The Role of Vascular Amyloid in the Age of Aducanumab

Stroke ◽  
2021 ◽  
Author(s):  
Lukas Sveikata ◽  
Andreas Charidimou ◽  
Anand Viswanathan
Keyword(s):  
Clinical Trials ◽  
Alzheimer Disease ◽  
Cerebral Amyloid Angiopathy ◽  
Amyloid Β ◽  
High Rate ◽  
Amyloid Angiopathy ◽  
Cerebrovascular Pathology ◽  
Cerebral Amyloid

We review the implications of the recently approved aducanumab amyloid-β immunotherapy for treating Alzheimer disease with comorbid cerebral amyloid angiopathy. In clinical trials, amyloid-β immunotherapy has been associated with a high rate of amyloid-related imaging abnormalities, potentially driven by coexisting cerebral amyloid angiopathy. Therefore, immunotherapy’s efficacy in patients may be modified by coexisting cerebrovascular pathology. We discuss the contributions of cerebral amyloid angiopathy on the development of amyloid-related imaging abnormalities and propose strategies to identify cerebral amyloid angiopathy in patients considered for immunotherapy.

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