title: Effects of Hypertension and Anti-Hypertensive Treatment on Amyloid-β (Aβ) Plaque Load and Aβ-Synthesizing and Aβ-Degrading Enzymes in Frontal Cortex.
abstract: Epidemiological data associate hypertension with a predisposition to Alzheimer's disease (AD), and a number of postmortem and in vivo studies also demonstrate that hypertension increases amyloid-β (Aβ) pathology. In contrast, anti-hypertensive medications reportedly improve cognition and decrease the risk of AD, while certain classes of anti-hypertensive drugs are associated with decreased AD-related pathology. We investigated the effects of hypertension and anti-hypertensive treatment on Aβ plaque load in postmortem frontal cortex in AD. Aβ load was significantly increased in hypertensive (n = 20) relative to normotensive cases (n = 62) and was also significantly higher in treated (n = 9) than untreated hypertensives (n = 11). We then looked into mechanisms by which hypertension and treatment might increase Aβ load, focusing on Aβ-synthesizing enzymes, β- and γ-secretase, and Aβ-degrading enzymes, angiotensin-converting enzyme (ACE), insulin-degrading enzyme (IDE) and neprilysin. ACE and IDE protein levels were significantly lower in hypertensive (n = 21) than normotensive cases (n = 64), perhaps translating to decreased Aβ catabolism in hypertensives. ACE level was significantly higher in treated (n = 9) than untreated hypertensives (n = 12), possibly reflecting feedback upregulation of the renin-angiotensin system. Prospective studies in larger cohorts stratified according to anti-hypertensive drug class are needed to confirm these initial findings and to elucidate the interactions between hypertension, anti-hypertensive treatments, and Aβ metabolism.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Ashby
authors.forename: James S
authors.initials: JS
authors.lastname: Miners
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Kehoe
authors.forename: Seth
authors.initials: S
authors.lastname: Love
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry; D007339:Insulysin / Q000378:metabolism; D008297:Male; D015260:Neprilysin / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D012189:Retrospective Studies
chemical_list: D000959:Antihypertensive Agents; D053829:Amyloid Precursor Protein Secretases; D007703:Peptidyl-Dipeptidase A; D015260:Neprilysin; D007339:Insulysin
keywords: Alzheimer’s disease; Angiotensin-converting enzyme; BACE; amyloid β protein; anti-hypertensive; hypertension; insulin-degrading enzyme; β-secretase; γ-secretase