Non-neuronal and neuronal BACE1 elevation in association with angiopathic and leptomeningeal β-amyloid deposition in the human brain.
BACKGROUND
Cerebral amyloid angiopathy (CAA) refers to the deposition of β-amyloid (Aβ) peptides in the wall of brain vasculature, commonly involving capillaries and arterioles. Also being considered a part of CAA is the Aβ deposition in leptomeninge. The cellular origin of angiopathic Aβ and the pathogenic course of CAA remain incompletely understood.


METHODS
The present study was aimed to explore the pathogenic course of CAA in the human cerebrum via examination of changes in β-secretase-1 (BACE1), the obligatory Aβ producing enzyme, relative to Aβ and other cellular markers, by neuroanatomical and biochemical characterizations with postmortem brain samples and primary cell cultures.


RESULTS
Immunoreactivity (IR) for BACE1 was essentially not visible at vasculature in cases without cerebral amyloidosis (control group, n = 15, age = 86.1 ± 10.3 year). In cases with brain amyloid pathology (n = 15, age = 78.7 ± 12.7 year), increased BACE1 IR was identified locally at capillaries, arterioles and along the pia, localizing to endothelia, perivascular dystrophic neurites and meningeal cells, and often coexisting with vascular iron deposition. Double immunofluorescence with densitometric analysis confirmed a site-specific BACE1 elevation at cerebral arterioles in the development of vascular Aβ deposition. Levels of BACE1 protein, activity and its immediate product (C99) were elevated in leptomeningeal lysates from cases with CAA relative to controls. The expression of BACE1 and other amyloidogenic proteins in the endothelial and meningeal cells was confirmed in primary cultures prepared from human leptomeningeal and arteriolar biopsies.


CONCLUSIONS
These results suggest that BACE1 elevation in the endothelia and perivascular neurites may be involved in angiopathic Aβ deposition, while BACE1 elevation in meningeal cells might contribute Aβ to leptomeningeal amyloidosis.
Department of Anatomy and Neurobiology, Central South University School of Basic Medical Science, Changsha, Hunan, 410013, China. kxglsjs@126.com.|Department of Anatomy, Xinjiang Medical University, Urumqi, Xinjiang, 830011, China. kxglsjs@126.com.
Zhi-Qin
ZQ
Xue
Central South University Affiliated Tumor Hospital, Changsha, Hunan, 410006, China. hezhw2001@163.com.
Zheng-Wen
ZW
He
Central South University Affiliated Tumor Hospital, Changsha, Hunan, 410006, China. dryujianjun@sina.com.
Jian-Jun
JJ
Yu
Department of Anatomy and Neurobiology, Central South University School of Basic Medical Science, Changsha, Hunan, 410013, China. caojicyan@csu.edu.cn.
Yan
Y
Cai
Department of Human Anatomy, Histology and Embryology, Institute of Basic Medical Sciences, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, 100730, China. qiuwy73@126.com.
Wen-Ying
WY
Qiu
Department of Anatomy and Neurobiology, Central South University School of Basic Medical Science, Changsha, Hunan, 410013, China. panaihua@csu.edu.cn.
Aihua
A
Pan
Department of Surgery and Centre for Neuroscience, Flinders University School of Medicine, Bedford Park, SA, 5042, Australia. weiping.gai@flinders.edu.au.
Wei-Ping
WP
Gai
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA. caih@mail.nih.gov.
Huaibin
H
Cai
Department of Anatomy and Neurobiology, Central South University School of Basic Medical Science, Changsha, Hunan, 410013, China. luoxuegang@csu.edu.cn.
Xue-Gang
XG
Luo
Department of Human Anatomy, Histology and Embryology, Institute of Basic Medical Sciences, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, 100730, China. mcpumc@163.com.
Chao
C
Ma
Department of Anatomy and Neurobiology, Central South University School of Basic Medical Science, Changsha, Hunan, 410013, China. yanxiaoxin@csu.edu.cn.
Xiao-Xin
XX
Yan
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000686:Amyloidosis / Q000378:metabolism* / Q000473:pathology; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D002536:Cerebral Arteries / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008578:Meninges / Q000378:metabolism* / Q000473:pathology
D016229:Amyloid beta-Peptides; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human