Cerebrospinal Fluid Changes in the Renin-Angiotensin System in Alzheimer’s Disease

Article type: Research Article

Authors: Kehoe, Patrick G.^a | Al Mulhim, Noura^a | Zetterberg, Henrik^{b; c; d; e} | Blennow, Kaj^{b; c} | Miners, James S.^{a; *}

Affiliations: [a] Dementia Research Group, Clinical Neuroscience, Southmead Hospital, University of Bristol, Bristol, UK | [b] Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden | [c] Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden | [d] Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK | [e] UK Dementia Research Institute at UCL, London, UK

Correspondence: [*] Correspondence to: Scott Miners, Dementia Research Group, University of Bristol, Level 1, Learning and Research, Southmead Hospital, Bristol BS10 5NB, UK. Tel.: +44 117 4147818; Fax: +44 117 9753760; E-mail: Scott.Miners@bristol.ac.uk.

Abstract: Observations in autopsied brain tissue indicate that overactivation of the classical renin-angiotensin system (cRAS) and underactivity within regulatory RAS pathways (rRAS) are associated with pathology in Alzheimer’s disease (AD). The primary aim of this study was to investigate whether cerebrospinal fluid (CSF) markers of RAS are altered in AD in relation to established CSF markers of disease pathology (lower Aβ42 and elevated tau) and CSF markers of capillary dysfunction. We studied 40 controls and 40 AD cases grouped according to a biomarker profile (i.e., AD cases t-tau>400 pg/mL, pTau >60 pg/mL, and Aβ42 <550 pg/mL). Angiotensin-II converting enyme-1 (ACE1) and ACE2 enzyme activity was measured using fluorogenic peptide substrates; sPDGFRβ and albumin level by sandwich ELISA; and angiotensin-I (Ang-I), Ang-II, and Ang-(1-7) by direct ELISA. CSF Aβ42, total, and phosphorylated tau levels were previously measured by INNOTEST sandwich ELISA. CSF ACE1 activity was significantly elevated in AD (p = 0.008) and positively correlated with ACE2 in AD (r = 0.420, p = 0.007). CSF ACE1 weakly correlated with t-tau (r = 0.294, p = 0.066) and p-tau (r = 0.329, p = 0.038) but not with Aβ42 in the controls but not in AD. ACE1 correlated positively with sPDGFRβ (r = 0.426, p = 0.007), a marker of pericyte injury, and ACE2 correlated positively with albumin (r = 0.422, p = 0.008), a marker of blood-brain barrier integrity. CSF Ang-I, Ang-II, and Ang-(1-7) levels were unchanged in AD. This cross-sectional CSF study indicates RAS dysfunction in relation to capillary damage in AD.

Keywords: Alzheimer’s disease, angiotensin-II, angiotensin-(1-7), angiotensin-II converting enyme-1 (ACE1), angiotensin-II converting enyme-2 (ACE2), cerebrospinal fluid, renin-angiotensin system

DOI: 10.3233/JAD-190721

Journal: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 525-535, 2019