Effects of Hypertension and Anti-Hypertensive Treatment on Amyloid-β (Aβ) Plaque Load and Aβ-Synthesizing and Aβ-Degrading Enzymes in Frontal Cortex

Emma L. Ashby, James S. Miners, Patrick G. Kehoe, Seth Love, Francesco Panza
2016 Journal of Alzheimer's Disease  
Epidemiological data associate hypertension with a predisposition to Alzheimer's disease (AD) and a number of post-mortem and in vivo studies also demonstrate that hypertension increases amyloid-beta (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
more » ... ve treatment on Aβ plaque load in post-mortem 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-synthesising enzymes, β-and γsecretase, and Aβ-degrading enzymes, angiotensin-converting enzyme (ACE), insulin-2 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 reninangiotensin system. Prospective studies in larger cohorts stratified according to antihypertensive drug class are needed to confirm these initial findings and to elucidate the interactions between hypertension, anti-hypertensive treatments and Aβ metabolism. Abbreviations: Aβ = amyloid-beta; AβPP = amyloid-beta precursor protein; ACE = angiotensin-converting enzyme; ACEI = angiotensin-converting enzyme inhibitor; AD = Alzheimer's disease; AngII = angiotensin II; ARB = angiotensin receptor blocker; BBB = blood brain barrier; CCB = calcium channel blocker; IDE = insulin-degrading enzyme; NEP = neprilysin; NFT = neurofibrillary tangle
doi:10.3233/jad-150831 pmid:26836178 fatcat:rjiu4up2bzacrc7oh2bh7hvddy