Differential effects of angiotensin II receptor blockers on Aβ generation

Angiotensin II receptor blockers (ARBs) are widely prescribed for the medication of systemic hypertension and congestive heart failure. It has been reported that ARBs can reduce the risk for the onset of Alzheimer's disease (AD) and have beneficial effects on dementia. Neurotoxic amyloid β-protein (Aβ) is believed to play a causative role in the development of AD. However, whether ARBs regulate Aβ generation remains largely unknown. Here, we studied the effect of ARBs on Aβ generation and found that telmisartan significantly increased Aβ40 and Aβ42 generation, but decreased the Aβ42/Aβ40 ratio. However, losartan, valsartan and candesartan did not increase Aβ generation, while olmesartan significantly increased Aβ42 generation. We also found that telmisartan increased the Aβ generation through angiotensin type 1a receptor (AT1a) and the receptor-related phosphotidylinositide 3-kinases (PI3K) pathway. Our findings revealed the different effects of ARBs on Aβ generation and provide new evidence for the relationship between antihypertensive treatment and AD pathogenesis.

[1]  H. Green,et al.  QUANTITATIVE STUDIES OF THE GROWTH OF MOUSE EMBRYO CELLS IN CULTURE AND THEIR DEVELOPMENT INTO ESTABLISHED LINES , 1963, The Journal of cell biology.

[2]  Jaakko Tuomilehto,et al.  The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. , 2002 .

[3]  R. Mayeux,et al.  Epidemiology of Alzheimer disease. , 2012, Cold Spring Harbor perspectives in medicine.

[4]  Jian-Mei Li,et al.  Inhibition of cognitive decline in mice fed a high-salt and cholesterol diet by the angiotensin receptor blocker, olmesartan , 2007, Neuropharmacology.

[5]  R. Havlik,et al.  The association between midlife blood pressure levels and late-life cognitive function. The Honolulu-Asia Aging Study. , 1995, JAMA.

[6]  T. Walther,et al.  Cardiovascular phenotype of mice lacking all three subtypes of angiotensin II receptors , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[7]  Q. Tong,et al.  Central Angiotensin II Stimulation Promotes β Amyloid Production in Sprague Dawley Rats , 2011, PloS one.

[8]  M. Nishida,et al.  Induction of Cardiac Fibrosis by β-Blocker in G Protein-independent and G Protein-coupled Receptor Kinase 5/β-Arrestin2-dependent Signaling Pathways* , 2012, The Journal of Biological Chemistry.

[9]  D. Dickson,et al.  Aβ40 Inhibits Amyloid Deposition In Vivo , 2007, The Journal of Neuroscience.

[10]  J. Hardy,et al.  Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. , 1996, Nature medicine.

[11]  M. Sasamata,et al.  Telmisartan has the strongest binding affinity to angiotensin II type 1 receptor: comparison with other angiotensin II type 1 receptor blockers. , 2005, International journal of clinical pharmacology research.

[12]  G. Schellenberg,et al.  Secreted amyloid β–protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease , 1996, Nature Medicine.

[13]  L. Hansson,et al.  Hypertension is related to cognitive impairment: a 20-year follow-up of 999 men. , 1998, Hypertension.

[14]  K. Zou,et al.  Amyloid β‐protein (Aβ)1–40 protects neurons from damage induced by Aβ1–42 in culture and in rat brain , 2003 .

[15]  B. Strooper,et al.  The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics , 2011, Nature Reviews Drug Discovery.

[16]  M. Kawaichi,et al.  A New Functional Screening System for Identification of Regulators for the Generation of Amyloid β-Protein* , 2002, The Journal of Biological Chemistry.

[17]  C. Ballard,et al.  Is a potential Alzheimer's therapy already in use for other conditions? Can medications for hypertension, diabetes and acne help with the symptoms? , 2013, Expert opinion on investigational drugs.

[18]  N. Tabet,et al.  Antihypertensives, angiotensin, glucose and Alzheimer’s disease , 2013, Expert review of neurotherapeutics.

[19]  P Whelton,et al.  Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988-1991. , 1995, Hypertension.

[20]  Donglin Zhu,et al.  Central angiotensin II‐induced Alzheimer‐like tau phosphorylation in normal rat brains , 2012, FEBS letters.

[21]  M. White,et al.  YMXM motifs of IRS-1 define substrate specificity of the insulin receptor kinase. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[22]  W. Markesbery,et al.  Brain infarction and the clinical expression of Alzheimer disease. , 1997, JAMA.

[23]  J. Saavedra,et al.  Telmisartan directly ameliorates the neuronal inflammatory response to IL-1β partly through the JNK/c-Jun and NADPH oxidase pathways , 2012, Journal of Neuroinflammation.

[24]  W. Elliott.  Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis , 2011 .

[25]  W. Markesbery,et al.  Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. , 1997, JAMA.

[26]  M. Mogi,et al.  Cognitive Deficit in Amyloid-&bgr;–Injected Mice Was Improved by Pretreatment With a Low Dose of Telmisartan Partly Because of Peroxisome Proliferator-Activated Receptor-&ggr; Activation , 2009, Hypertension.

[27]  E. Schiffrin,et al.  Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin II in vascular smooth muscle cells. , 2000, Pharmacological reviews.

[28]  K. Catt,et al.  Angiotensin receptors and their antagonists. , 1996, The New England journal of medicine.

[29]  Qian-Li Xue,et al.  Antihypertensive drugs decrease risk of Alzheimer disease , 2013, Neurology.

[30]  K. Zou,et al.  Amyloid beta-protein (Abeta)1-40 protects neurons from damage induced by Abeta1-42 in culture and in rat brain. , 2003, Journal of neurochemistry.

[31]  R. Sodhi,et al.  An update on non-peptide angiotensin receptor antagonists and related RAAS modulators. , 2007, Life sciences.

[32]  S. Goyal,et al.  Telmisartan, a dual ARB/partial PPAR‐γ agonist, protects myocardium from ischaemic reperfusion injury in experimental diabetes , 2011, Diabetes, obesity & metabolism.

[33]  D. Diz,et al.  Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT1a Receptors in Mouse Brain , 2006, Hypertension.