Physiological clearance of amyloid-beta by the kidney and its therapeutic potential for Alzheimer’s disease

Tian, Ding-Yuan; Cheng, Yuan; Zhuang, Zhen-Qian; He, Chenyang; Pan, Qian-Guang; Tang, Mingshuang; Hu, Xuelian; Shen, Yujie; Wang, Ye‐Ran; Chen, Sihan; Sun, Hao‐Lun; Sun, Pu‐Yang; Yu, Zhongyuan; Fan, Dong-Yu; Bu, Xian‐Le; Tan, Cheng‐Rong; Zeng, Guihua; Wang, Jun; Zhao, Hongwen; Wang, Yanjiang

doi:10.1038/s41380-021-01073-6

Cited by 56 publications

(60 citation statements)

References 34 publications

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“…The role of beta-amyloid (Aβ) pathology in the relationship between CKD and cognitive decline in poorly understood. Serum Aβ levels have been shown to be significantly higher in CKD patients, possibly related to reduced renal clearance of Aβ protein from peripheral blood (129). Cystatin-C, a low-molecular weight protein that is used to estimate GFR, has also been demonstrated to colocalize with beta-amyloid in the brain (130).…”

Section: Beta-amyloid Pathologymentioning

confidence: 99%

Disentangling the Relationship Between Chronic Kidney Disease and Cognitive Disorders

Kelly

Rothwell

2022

Front. Neurol.

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Chronic kidney disease (CKD) is a rapidly rising global health burden that affects nearly 40% of older adults. Epidemiologic data suggest that individuals at all stages of chronic kidney disease (CKD) have a higher risk of developing cognitive disorders and dementia, and thus represent a vulnerable population. It is currently unknown to what extent this risk may be attributable to a clustering of traditional risk factors such as hypertension and diabetes mellitus leading to a high prevalence of both symptomatic and subclinical ischaemic cerebrovascular lesions, or whether other potential mechanisms, including direct neuronal injury by uraemic toxins or dialysis-specific factors could also be involved. These knowledge gaps may lead to suboptimal prevention and treatment strategies being implemented in this group. In this review, we explore the mechanisms of susceptibility and risk in the relationship between CKD and cognitive disorders.

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Section: Beta-amyloid Pathologymentioning

confidence: 99%

Disentangling the Relationship Between Chronic Kidney Disease and Cognitive Disorders

Kelly

Rothwell

2022

Front. Neurol.

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“…The accumulation of these peptides forms aggregates (fibrils) that may further assemble into plaques ( 24 , 135 ). The kidney regulates Aβ clearance in the blood, which suggests that kidney dysfunction may play role in the accumulation of Aβ in CKD ( 136 ). The SARS-CoV-2 spike protein also binds Aβ ( 137 ), which increases infection and reduces Aβ clearance ( 138 ).…”

Section: Amyloid-beta (Aβ)mentioning

confidence: 99%

RAGE pathway activation and function in chronic kidney disease and COVID-19

Curran

Kopp

2022

Front. Med.

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The multi-ligand receptor for advanced glycation end-products (RAGE) and its ligands are contributing factors in autoimmunity, cancers, and infectious disease. RAGE activation is increased in chronic kidney disease (CKD) and coronavirus disease 2019 (COVID-19). CKD may increase the risk of COVID-19 severity and may also develop in the form of long COVID. RAGE is expressed in essentially all kidney cell types. Increased production of RAGE isoforms and RAGE ligands during CKD and COVID-19 promotes RAGE activity. The downstream effects include cellular dysfunction, tissue injury, fibrosis, and inflammation, which in turn contribute to a decline in kidney function, hypertension, thrombotic disorders, and cognitive impairment. In this review, we discuss the forms and mechanisms of RAGE and RAGE ligands in the kidney and COVID-19. Because various small molecules antagonize RAGE activity in animal models, targeting RAGE, its co-receptors, or its ligands may offer novel therapeutic approaches to slowing or halting progressive kidney disease, for which current therapies are often inadequate.

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“…The kidney is considered to be one of the major peripheral organs for Aβ clearance in both human and animal studies [6,24]. Recently, Tian and colleagues showed that the kidney removed Aβ from the blood, and proposed the pathophysiological significance of the renal clearance of Aβ in mammals [25]. We observed a similar clearance as a consequence of Aβ in the zebrafish pronephros (Figure 2), a functional kidney counterpart in the larval stages consisting of the glomerulus and bilateral pronephric tubules fused with the vascular structure at the midline [26].…”

Section: Cleared Maβ42 Accumulates In the Pronephros Via Blood Flowmentioning

confidence: 99%

Differential Clearance of Aβ Species from the Brain by Brain Lymphatic Endothelial Cells in Zebrafish

Jeong

Lee

Cho

et al. 2021

IJMS

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The failure of amyloid beta (Aβ) clearance is a major cause of Alzheimer’s disease, and the brain lymphatic systems play a crucial role in clearing toxic proteins. Recently, brain lymphatic endothelial cells (BLECs), a non-lumenized lymphatic cell in the vertebrate brain, was identified, but Aβ clearance via this novel cell is not fully understood. We established an in vivo zebrafish model using fluorescently labeled Aβ42 to investigate the role of BLECs in Aβ clearance. We discovered the efficient clearance of monomeric Aβ42 (mAβ42) compared to oligomeric Aβ42 (oAβ42), which was illustrated by the selective uptake of mAβ42 by BLECs and peripheral transport. The genetic depletion, pharmacological inhibition via the blocking of the mannose receptor, or the laser ablation of BLECs resulted in the defective clearance of mAβ42. The treatment with an Aβ disaggregating agent facilitated the internalization of oAβ42 into BLECs and improved the peripheral transport. Our findings reveal a new role of BLECs in the differential clearance of mAβ42 from the brain and provide a novel therapeutic strategy based on promoting Aβ clearance.

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Physiological clearance of amyloid-beta by the kidney and its therapeutic potential for Alzheimer’s disease

Cited by 56 publications

References 34 publications

Disentangling the Relationship Between Chronic Kidney Disease and Cognitive Disorders

Disentangling the Relationship Between Chronic Kidney Disease and Cognitive Disorders

RAGE pathway activation and function in chronic kidney disease and COVID-19

Differential Clearance of Aβ Species from the Brain by Brain Lymphatic Endothelial Cells in Zebrafish

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