ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer's disease

被引:112
作者
Evans, Charles E. [1 ,2 ]
Miners, James S. [3 ]
Piva, Giulia [2 ]
Willis, Christine L. [4 ]
Heard, David M. [4 ]
Kidd, Emma J. [2 ]
Good, Mark A. [1 ]
Kehoe, Patrick G. [3 ]
机构
[1] Cardiff Univ, Sch Psychol, Cardiff CF10 3AT, S Glam, Wales
[2] Cardiff Univ, Sch Pharm & Pharmaceut Sci, Cardiff CF10 3NB, S Glam, Wales
[3] Univ Bristol, Translat Hlth Sci, Dementia Res Grp, Bristol Med Sch,Southmead Hosp, Level 1 Learning & Res, Bristol BS10 5NB, Avon, England
[4] Univ Bristol, Sch Chem, Bristol BS8 1TS, Avon, England
关键词
Alzheimer's disease; Renin-angiotensin system; ACE2; MasR; DIZE; Angiotensin-(1-7); ANGIOTENSIN-CONVERTING ENZYME; ANTIHYPERTENSIVE DRUGS; TAU PHOSPHORYLATION; GENDER-DIFFERENCES; RECEPTOR BLOCKERS; MEMORY; BETA; SYSTEM; BRAIN; ASSOCIATION;
D O I
10.1007/s00401-019-02098-6
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Mid-life hypertension and cerebrovascular dysfunction are associated with increased risk of later life dementia, including Alzheimer's disease (AD). The classical renin-angiotensin system (cRAS), a physiological regulator of blood pressure, functions independently within the brain and is overactive in AD. cRAS-targeting anti-hypertensive drugs are associated with reduced incidence of AD, delayed onset of cognitive decline, and reduced levels of A beta and tau in both animal models and human pathological studies. cRAS activity is moderated by a downstream regulatory RAS pathway (rRAS), which is underactive in AD and is strongly associated with pathological hallmarks in human AD, and cognitive decline in animal models of CNS disease. We now show that enhancement of brain ACE2 activity, a major effector of rRAS, by intraperitoneal administration of diminazene aceturate (DIZE), an established activator of ACE2, lowered hippocampal A beta and restored cognition in mid-aged (13-14-month-old) symptomatic Tg2576 mice. We confirmed that the protective effects of DIZE were directly mediated through ACE2 and were associated with reduced hippocampal soluble A beta(42) and IL1-beta levels. DIZE restored hippocampal MasR levels in conjunction with increased NMDA NR2B and downstream ERK signalling expression in hippocampal synaptosomes from Tg2576 mice. Chronic (10 weeks) administration of DIZE to pre-symptomatic 9-10-month-old Tg2576 mice, and acute (10 days) treatment in cognitively impaired 12-13-month-old mice, prevented the development of cognitive impairment. Together these data demonstrate that ACE2 enhancement protects against and reverses amyloid-related hippocampal pathology and cognitive impairment in a preclinical model of AD.
引用
收藏
页码:485 / 502
页数:18
相关论文
共 92 条
[1]   Modulation of brain ACE and ACE2 may be a promising protective strategy against cerebral ischemia/reperfusion injury: an experimental trial in rats [J].
Abdel-Fattah, Maha Mohammed ;
Messiha, Basim Anwar Shehata ;
Mansour, Ahmed Mohamed .
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 2018, 391 (09) :1003-1020
[2]   Increased aggression in males in transgenic Tg2576 mouse model of Alzheimer's disease [J].
Alexander, Gaukhman ;
Hanna, Amanda ;
Serna, Vanida ;
Younkin, Linda ;
Younkin, Steve ;
Janus, Christopher .
BEHAVIOURAL BRAIN RESEARCH, 2011, 216 (01) :77-83
[3]   Current status of renin-aldosterone angiotensin system-targeting anti-hypertensive drugs as therapeutic options for Alzheimer's disease [J].
Ashby, Emma Louise ;
Kehoe, Patrick G. .
EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2013, 22 (10) :1229-1242
[4]   Assessing white matter ischemic damage in dementia patients by measurement of myelin proteins [J].
Barker, Rachel ;
Wellington, Dannielle ;
Esiri, Margaret M. ;
Love, Seth .
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 2013, 33 (07) :1050-1057
[5]   ANGIOTENSIN CONVERTING ENZYME DENSITY IS INCREASED IN TEMPORAL CORTEX FROM PATIENTS WITH ALZHEIMERS-DISEASE [J].
BARNES, NM ;
CHENG, CHK ;
COSTALL, B ;
NAYLOR, RJ ;
WILLIAMS, TJ ;
WISCHIK, CM .
EUROPEAN JOURNAL OF PHARMACOLOGY, 1991, 200 (2-3) :289-292
[6]   Facilitation of Hippocampal Synaptogenesis and Spatial Memory by C-Terminal Truncated Nle1-Angiotensin IV Analogs [J].
Benoist, Caroline C. ;
Wright, John W. ;
Zhu, Mingyan ;
Appleyard, Suzanne M. ;
Wayman, Gary A. ;
Harding, Joseph W. .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2011, 339 (01) :35-44
[7]   ACE2 activator diminazene aceturate reduces adiposity but preserves lean mass in young and old rats [J].
Bruce, Erin B. ;
Sakarya, Yasemin ;
Kirichenko, Nataliya ;
Toklu, Hale Z. ;
Sumners, Colin ;
Morgan, Drake ;
Tumer, Nihal ;
Scarpace, Philip J. ;
Carter, Christy S. .
EXPERIMENTAL GERONTOLOGY, 2018, 111 :133-140
[8]   Molecular Interplay between Mammalian Target of Rapamycin (mTOR), Amyloid-β, and Tau EFFECTS ON COGNITIVE IMPAIRMENTS [J].
Caccamo, Antonella ;
Majumder, Smita ;
Richardson, Arlan ;
Strong, Randy ;
Oddo, Salvatore .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (17) :13107-13120
[9]  
CHAPPELL MC, 1989, J BIOL CHEM, V264, P16518
[10]   Substrate-based design of the first class of angiotensin-converting enzyme-related carboxypeptidase (ACE2) inhibitors [J].
Dales, NA ;
Gould, AE ;
Brown, JA ;
Calderwood, EF ;
Guan, B ;
Minor, CA ;
Gavin, JM ;
Hales, P ;
Kaushik, VK ;
Stewart, M ;
Tummino, PJ ;
Vickers, CS ;
Ocain, TD ;
Patane, MA .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2002, 124 (40) :11852-11853