Short Term Exposure to Bilirubin Induces Encephalopathy Similar to Alzheimer’s Disease in Late Life

Chen, Haoyu; Liang, Lu; Xu, Hua; Xu, Jia; Yao, Leyi; Li, Yanling; Tan, Yufan; Li, Xiaofen; Huang, Qianru; Yang, Zhenjun; Wu, Jiawen; Chen, Jinghong; Huang, Hongbiao; Wang, Xuejun; Zhang, Chang E.; Liu, Jinbao

doi:10.3233/jad-190945

Cited by 10 publications

(12 citation statements)

References 48 publications

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“…These results suggest that the probability for unconjugated bilirubin that can freely cross the BBB under certain conditions such as hypoxia and infection to gain access to the CNS is significantly higher in dementia patients with Aβ deposition. Our results provide further evidence to support our previous finding in primary hippocampal neurons and in animal models, showing that bilirubin could induce Aβ deposition and formation (Chen et al, 2020). Consistent with these experimental and clinical findings, our intervention study shows that intravenous supplementation of human albumin at a dose of 10 g every 2 weeks for 24 weeks yields benefit on daily function and dementia severity in AD patients.…”

Section: Resultssupporting

confidence: 91%

“…Our crosssectional case-controlled study indicates that increased IBIL concentrations and a greater IBIL/ALB ratio are particularly segregated with the dementia with Aβ deposition patients. These results, in combination with our findings in primary hippocampal neurons and in animal models (Chen et al, 2020), suggest that increased serum concentrations of IBIL may play an important role in the etiology of dementia with Aβ deposition.…”

Section: Discussionsupporting

confidence: 84%

“…Clinically relevant elevation of bilirubin concentrations can act as an endogenous proteasome inhibitor and inhibit UPS-mediated protein degradation, which may affect the degradation of Aβ and lead to its abnormal accumulation (Hong et al, 2014). In addition, our prior study using primary hippocampal neurons and animal models has shown that bilirubin induces Aβ deposition and formation, and tau hyperphosphorylation, by activating GSK-3β, CDK5, and JNK, increasing the expression of amyloid-β protein precursor (AβPP) γ-secretase PS2, and decreasing the expression of α-secretase ADAM17 (Chen et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…Despite the challenges associated with combating the pathological change in symptomatic AD patients, more efforts need to be made to identify new therapeutic approaches. Bilirubin induces Aβ deposition and tau hyperphosphorylation, resulting in AD-like learning and memory injuries in animal models ( Chen et al, 2020 ). We hypothesize that measures to down-regulate bilirubin concentrations in the central nervous system (CNS) may have clinical benefits on improving the cognitive and behavioral functions of AD patients.…”

Section: Introductionmentioning

confidence: 99%

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Abnormal Serum Bilirubin/Albumin Concentrations in Dementia Patients With Aβ Deposition and the Benefit of Intravenous Albumin Infusion for Alzheimer’s Disease Treatment

et al. 2020

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Background: Our previous study in animal models revealed that bilirubin could induce Aβ formation and deposition. Bilirubin may be important in neurodegenerative dementia with Aβ deposition. Hence, lowering the concentration of the free bilirubin capable of crossing the blood brain-barrier may benefit the treatment of Alzheimer's disease (AD). Objectives: The objectives of this study were to examine the change in the serum bilirubin and albumin concentrations of dementia patients with Aβ deposition, and to determine the effects of intravenous administration of albumin in the treatment of AD. Methods: Bilirubin and albumin concentrations in dementia patients with Aβ deposition were examined. Cell viability and apoptosis were determined in dopaminergic neuronlike cells MN9D treated with bilirubin in the presence of diverse concentrations of serum. Human albumin at a dose of 10 g every 2 weeks for 24 weeks was administered intravenously to AD patients to examine the effect of albumin on AD symptoms. Results: Significantly higher indirect bilirubin (IBIL) concentrations, lower albumin concentrations, and higher ratio of IBIL to albumin (IBIL/ALB) were observed in dementia patients with Aβ deposition, including AD, dementia with Lewy bodies, and general paresis of insane. In vitro assays showed that bilirubin-induced injury in cultured dopaminergic neuron-like cells negatively depends on the concentration of serum in the culture medium. General linear model with repeated measures analysis indicated a main effect of group on the change in albumin concentrations and Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL) scores, and the main effect of time and group, and group-by-time interaction on the change of Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) scores. Analysis of the combined data

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Section: Resultssupporting

confidence: 91%

Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Abnormal Serum Bilirubin/Albumin Concentrations in Dementia Patients With Aβ Deposition and the Benefit of Intravenous Albumin Infusion for Alzheimer’s Disease Treatment

et al. 2020

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“…As a curiosity, in obstructive jaundice, miR-21 and miR-125b, among others, were found upregulated in the mouse liver ( Kanda et al., 2010 ) and the later associated with increased tau hyperphosphorylation ( Banzhaf-Strathmann et al., 2014 ; Zhang et al., 2019 ). Again, exposure to bilirubin early in life in newborn rats was suggested to promote AD-like pathological changes later in life, including tau protein hyperphosphorylation, Aβ production and spatial learning and memory injuries ( Chen et al., 2019 ), pointing to the significance of microglial priming in jaundiced infants during the neonatal period.…”

Section: Discussionmentioning

confidence: 99%

Microglia Susceptibility to Free Bilirubin Is Age-Dependent

et al. 2020

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Increased concentrations of unconjugated bilirubin (UCB), namely its free fraction (Bf), in neonatal life may cause transient or definitive injury to neurons and glial cells. We demonstrated that UCB damages neurons and glial cells by compromising oligodendrocyte maturation and myelination, and by activating astrocytes and microglia. Immature neurons and astrocytes showed to be especially vulnerable. However, whether microglia susceptibility to UCB is also age-related was never investigated. We developed a microglia culture model in which cells at 2 days in vitro (2DIV) revealed to behave as the neonatal microglia (amoeboid/reactive cells), in contrast with those at 16DIV microglia that performed as aged cells (irresponsive/dormant cells). Here, we aimed to unveil whether UCB-induced toxicity diverged from the young to the long-cultured microglia. Cells were isolated from the cortical brain of 1-to 2-day-old CD1 mice and incubated for 24 h with 50/100 nM Bf levels, which were associated to moderate and severe neonatal hyperbilirubinemia, respectively. These concentrations of Bf induced early apoptosis and amoeboid shape in 2DIV microglia, while caused late apoptosis in 16DIV cells, without altering their morphology. CD11b staining increased in both, but more markedly in 2DIV cells. Likewise, the gene expression of HMGB1, a well-known alarmin, as well as HMGB1 and GLT-1-positive cells, were enhanced as compared to longmaturated microglia. The CX3CR1 reduction in 2DIV microglia was opposed to the 16DIV cells and suggests a preferential Bf-induced sickness response in younger cells. In conformity, increased mitochondrial mass and NO were enhanced in 2DIV cells, but unchanged or reduced, respectively, in the 16DIV microglia. However, 100 nM Bf caused iNOS gene overexpression in 2DIV and 16DIV cells. While only arginase 1/IL-1b gene expression levels increased upon 50/100 nM Bf treatment in long-maturated microglia, MHCII/arginase 1/TNF-a/IL-1b/IL-6 (>10-fold) were upregulated in the 2DIV microglia. Remarkably, enhanced inflammatory-associated microRNAs (miR-155/miR-125b/miR-21/miR-146a) and reduced anti-inflammatory miR-124 were found in young microglia by both Bf concentrations, while remained unchanged (miR/21/miR-125b) or decreased (miR-155/miR-146a/miR-124) in aged cells. Altogether, these findings support the neurodevelopmental susceptibilities to UCB-induced neurotoxicity, the most severe

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Age‐related cognitive decline is accelerated in alcohol use disorder

Kurihara,

Shiroma,

Koda

et al. 2023

Neuropsychopharm Rep

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This study aimed to examine potential cognitive impairments in patients with alcohol use disorder (AUD), and explore the factors affecting them. We recruited 97 inpatients with AUD, showing superficially normal cognitive function (mini‐mental state examination score ≥24) for this study. We assessed cognitive function after a 4‐week post‐abstinence period using the Brief Assessment of Cognition in Schizophrenia‐Japanese version (BACS‐J). Relationships between BACS‐J subcategory/composite raw scores and Z‐scores (deviation from standard data in healthy Japanese) and background factors such as age, sex, education, smoking status, mini‐mental state examination score, body mass index, systolic blood pressure, severity of depression, alcohol consumption, and laboratory findings were analyzed. Multiple regression analysis showed that the age (p < 0.001) and total bilirubin level (p = 0.014) were worsening factors for the BACS‐J composite raw score, whereas education (p < 0.001) was a protective factor. An inverse correlation was apparent between the age and the composite Z‐score of the BACS‐J (r = −0.431, p < 0.001). Receiver operating characteristic (ROC) analysis identified 53 years as the cutoff age for predicting more than −2SD cognitive decline from the normal standard, with a high negative predictive value (95%). Patients with AUD aged ≥53 years showed more pronounced impairments in verbal memory, working memory, verbal fluency, and attention than those younger than 53 years (p < 0.05). These findings clearly demonstrate accelerated age‐related cognitive decline in patients with AUD, especially those aged ≥53 years, suggesting the necessity of early intervention in patients with AUD to prevent progressive cognitive impairment and preserve their quality of life.

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Short Term Exposure to Bilirubin Induces Encephalopathy Similar to Alzheimer’s Disease in Late Life

Cited by 10 publications

References 48 publications

Abnormal Serum Bilirubin/Albumin Concentrations in Dementia Patients With Aβ Deposition and the Benefit of Intravenous Albumin Infusion for Alzheimer’s Disease Treatment

Abnormal Serum Bilirubin/Albumin Concentrations in Dementia Patients With Aβ Deposition and the Benefit of Intravenous Albumin Infusion for Alzheimer’s Disease Treatment

Microglia Susceptibility to Free Bilirubin Is Age-Dependent

Age‐related cognitive decline is accelerated in alcohol use disorder

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