High affinity of β-amyloid proteins to cerebral capillaries: implications in chronic lead exposure-induced neurotoxicity in rats

Fluids and Barriers of the CNS

Research

Huiying Gu¹  Yansheng Du¹  Wei Zheng²  Luke L. Liu²  Gang Zhao³  Xiaoli Shen⁴ 

[1] Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA;School of Health Sciences, Purdue University, 550 Stadium Mall Drive, HAMP-1273, 47907, West Lafayette, IN, USA;School of Health Sciences, Purdue University, 550 Stadium Mall Drive, HAMP-1273, 47907, West Lafayette, IN, USA;Department of Medical Biology, School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, China;School of Health Sciences, Purdue University, 550 Stadium Mall Drive, HAMP-1273, 47907, West Lafayette, IN, USA;School of Public Health, Qingdao University, Qingdao, China;

关键词: Lead (Pb);    Amyloid beta (Aβ);    Cerebral vasculature;    Low density lipoprotein receptor-related protein 1 (LRP1);   

DOI  :  10.1186/s12987-023-00432-5

 received in 2022-12-09, accepted in 2023-04-10,  发布年份 2023

来源: Springer

【 摘 要 】

Lead (Pb) is a known environmental risk factor in the etiology of Alzheimer’s disease (AD). The existing reports suggest that Pb exposure increases beta-amyloid (Aβ) levels in brain tissues and cerebrospinal fluid (CSF) and facilitates the formation of amyloid plaques, which is a pathological hallmark for AD. Pb exposure has long been associated with cerebral vasculature injury. Yet it remained unclear if Pb exposure caused excessive Ab buildup in cerebral vasculature, which may damage the blood–brain barrier and cause abnormal Ab accumulation. This study was designed to investigate the impact of chronic Pb exposure on Aβ accumulation in cerebral capillary and the expression of low-density lipoprotein receptor protein-1 (LRP1), a critical Aβ transporter, in brain capillary and parenchyma. Sprague–Dawley rats received daily oral gavage at doses of 0, 14 (low-dose), and 27 (high-dose) mg Pb/kg as Pb acetate, 5 d/wk, for 4 or 8 wks. At the end of Pb exposure, a solution containing Aβ40 was infused into the brain via the cannulated internal carotid artery. Data by ELISA showed a strikingly high affinity of Ab to cerebral vasculature, which was approximately 7–14 times higher than that to the parenchymal fractions collected from control brains. Pb exposure further aggravated the Aβ accumulation in cerebral vasculature in a dose-dependent manner. Western blot analyses revealed that Pb exposure decreased LRP1 expression in cortical capillaries and hippocampal parenchyma. Immunohistochemistry (IHC) studies further revealed a disrupted distribution of LRP1 alongside hippocampal vasculature accompanied with a decreased expression in hippocampal neurons by Pb exposure. Taken together, the current study demonstrated that the cerebral vasculature naturally possessed a high affinity to Aβ present in circulating blood. Pb exposure significantly increased Aβ accumulation in cerebral vasculature; such an increased Aβ accumulation was due partly to the diminished expression of LRP1 in response to Pb in tested brain regions. Perceivably, Pb-facilitated Ab aggravation in cerebral vasculature may contribute to Pb-associated amyloid alterations.

【 授权许可】

CC BY   
© The Author(s) 2023

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