Inhibition of angiotensin-converting enzyme (ACE) is a strategy used worldwide for managing hypertension. In addition to converting angiotensin I to angiotensin II, ACE also converts neurotoxic β-amyloid protein 42 (Aβ42) to Aβ40. Because of its neurotoxicity, Aβ42 is believed to play a causative role in the development of Alzheimer's disease (AD), whereas Aβ40 has neuroprotective effects against Aβ42 aggregation and also against metal-induced oxidative damage. Whether ACE inhibition enhances Aβ42 aggregation or impairs human cognitive ability are very important issues for preventing AD onset and for optimal hypertension management. In an 8-year longitudinal study, we found here that the mean intelligence quotient of male, but not female, hypertensive patients taking ACE inhibitors declined more rapidly than that of others taking no ACE inhibitors. Moreover, the sera of all AD patients exhibited a decrease in Aβ42-to-Aβ40–converting activity compared with sera from age-matched healthy individuals. Using human amyloid precursor protein transgenic mice, we found that a clinical dose of an ACE inhibitor was sufficient to increase brain amyloid deposition. We also generated human amyloid precursor protein/ACE+/− mice and found that a decrease in ACE levels promoted Aβ42 deposition and increased the number of apoptotic neurons. These results suggest that inhibition of ACE activity is a risk factor for impaired human cognition and for triggering AD onset.

To elucidate the mechanism of microglial migration across the blood–brain barrier (BBB), we developed an in vitro co-culture system and analysed real-time BBB integrity during transmigration. We show that ATP promotes microglia transmigration via a mechanism involving microglial matrix metalloproteinases (MMPs).

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Homocysteine-inducible endoplasmic reticulum (ER) protein (Herp) is an ER stress-inducible membrane protein involved in ER-associated degradation. Herp expression is maintained at low levels through a strict regulatory mechanism, but the details of this mechanism and the reasons why Herp expression is restricted in this manner remain unclear. Here, we show that Herp degradation involves synoviolin, an ER-resident E3 ubiquitin ligase. Herp protein levels were found to be markedly elevated in synoviolin-null cells, and Herp expression decreased when synoviolin was overexpressed. However, the lysine residues of Herp, which are ubiquitinated by E3 ubiquitin ligase, were not sufficient for regulation of Herp degradation. These results suggest that Herp degradation is mediated via synoviolin and that Herp ubiquitination involves amino acids other than lysine.