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

摘要

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 A beta(42) 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 A beta(42) <550 pg/mL). Angiotensin-II converting enyme-1 (ACE1) and ACE2 enzyme activity was measured using fluorogenic peptide substrates; sPDGFR beta and albumin level by sandwich ELISA; and angiotensin-I (Ang-I), Ang-II, and Ang-(1-7) by direct ELISA. CSF A beta(42), 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 A beta(42) in the controls but not in AD. ACE1 correlated positively with sPDGFR beta (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.