Background The function of medin, one of the most common human amyloid proteins that accumulates in the vasculature with aging, remains unknown. We aim to probe medin's role in cerebrovascular disease by comparing cerebral arterial medin content between cognitively normal and vascular dementia (VaD) patients and studying its effects on endothelial cell ( EC ) immune activation and neuroinflammation. We also tested whether monosialoganglioside‐containing nanoliposomes could reverse medin's adverse effects. Methods and Results Cerebral artery medin and astrocyte activation were measured and compared between VaD and cognitively normal elderly brain donors. EC s were exposed to physiologic dose of medin (5 μmol/L), and viability and immune activation (interleukin‐8, interleukin‐6, intercellular adhesion molecule‐1, and plasminogen activator inhibitor‐1) were measured without or with monosialoganglioside‐containing nanoliposomes (300 μg/ mL ). Astrocytes were exposed to vehicle, medin, medin‐treated EC s, or their conditioned media, and interleukin‐8 production was compared. Cerebral collateral arterial and parenchymal arteriole medin, white matter lesion scores, and astrocyte activation were higher in VaD versus cognitively normal donors. Medin induced EC immune activation (increased interleukin‐8, interleukin‐6, intercellular adhesion molecule‐1, and plasminogen activator inhibitor‐1) and reduced EC viability, which were reversed by monosialoganglioside‐containing nanoliposomes. Interleukin‐8 production was augmented when astrocytes were exposed to medin‐treated EC s or their conditioned media. Conclusions Cerebral arterial medin is higher in VaD compared with cognitively normal patients. Medin induces EC immune activation that modulates astrocyte activation, and its effects are reversed by monosialoganglioside‐containing nanoliposomes. Medin is a candidate novel risk factor for aging‐related cerebrovascular disease and VaD.

Medin causes human microvascular endothelial dysfunction through oxidative and nitrative stress and promotes pro-inflammatory signaling in endothelial cells. These effects appear to be mediated via RAGE. The findings represent a potential novel mechanism of vascular injury.

We tested whether nanoliposomes containing phosphatidylcholine, cholesterol and phosphatidic acid (NLPA) prevent bamyloid 1-42 (Ab42) fibrillation and Ab42-induced human arteriole endothelial dysfunction. NLPA abolished Ab42 fibril formation (thioflavin-T fluorescence/electron microscopy). In ex-vivo human adipose and leptomeningeal arterioles, Ab42 impaired dilator response to acetylcholine that was reversed by NLPA; this protection was abolished by L-NGnitroarginine methyl ester. Ab42 reduced human umbilical vein endothelial cell NO production that was restored by NLPA. Nanoliposomes prevented Ab42 amyloid formation, reversed Ab42-induced human microvascular endothelial dysfunction and may be useful in Alzheimer's disease.

BackgroundLight chain amyloidosis (AL) is associated with high mortality, especially in patients with advanced cardiovascular involvement. It is caused by toxicity of misfolded light chain proteins (LC) in vascular, cardiac, and other tissues. There is no treatment to reverse LC tissue toxicity. We tested the hypothesis that nanoliposomes composed of monosialoganglioside, phosphatidylcholine, and cholesterol (GM1 ganglioside–containing nanoliposomes [NLGM1]) can protect against LC‐induced human microvascular dysfunction and assess mechanisms behind the protective effect.Methods and ResultsThe dilator responses of ex vivo abdominal adipose arterioles from human participants without AL to acetylcholine and papaverine were measured before and after exposure to LC (20 μg/mL) with or without NLGM1 (1:10 ratio for LC:NLGM1 mass). Human umbilical vein endothelial cells were exposed for 18 to 20 hours to vehicle, LC with or without NLGM1, or NLGM1 and compared for oxidative and nitrative stress response and cellular viability. LC impaired arteriole dilator response to acetylcholine, which was restored by co‐treatment with NLGM1. LC decreased endothelial cell nitric oxide production and cell viability while increasing superoxide and peroxynitrite; these adverse effects were reversed by NLGM1. NLGM1 increased endothelial cell protein expression of antioxidant enzymes heme oxygenase 1 and NAD(P)H quinone dehydrogenase 1 and increased nuclear factor, erythroid 2 like 2 (Nrf‐2) protein. Nrf‐2 gene knockdown reduced antioxidant stress response and reversed the protective effects of NLGM1.ConclusionsNLGM1 protects against LC‐induced human microvascular endothelial dysfunction through increased nitric oxide bioavailability and reduced oxidative and nitrative stress mediated by Nrf‐2–dependent antioxidant stress response. These findings point to a potential novel therapeutic approach for light chain amyloidosis.

Introduction Medin, an aging‐associated amyloidogenic protein, induces cerebrovascular dysfunction and inflammation. We investigated the relationship between cerebrovascular medin and Alzheimer's disease (AD) and vascular dementia (VaD). Methods Cerebral arteriole medin was quantified from 91 brain donors with no dementia (ND), AD, VaD, or combined AD and VaD. Correlation analyses evaluated the relationship between arteriole medin, and plaques, tangles, or white matter lesions (WML). Receiver operating characteristic and regression analyses assessed whether medin is predictive of AD or VaD versus other cerebrovascular pathologies (circle of Willis [CoW] atherosclerosis and cerebral amyloid angiopathy [CAA]). Results Arteriole medin was higher in those with AD, VaD, or combined AD/VaD versus ND (P < .05), and correlated with tangle, plaque, and WML, but not CAA or CoW atherosclerosis. Among cerebrovascular pathologies, medin was the strongest predictor of AD diagnosis, whereas CoW atherosclerosis and arteriole medin were predictors of VaD. Discussion Cerebral arteriole medin is associated with and could be a potential novel risk factor or biomarker for AD and VaD.