27 October 2004. Because insulin degrading enzyme (IDE) also degrades Aβ (as well as the AβPP intracellular domain), it has come under intense scrutiny in AD research recently (see ARF related news story and Gabrielle Strobel's review of Aβ degradation studies). The relationship has led to the suggestion that low levels of IDE underlie the higher Aβ levels in AD and other diseases that feature β amyloid deposition, such as the cerebral amyloid angiopathies (CAA) (see ARF related news story). A report in the October 15 Journal of Biological Chemistry online seems to support that hypothesis, though in an indirect way. It is not the protein levels that are low, the authors report, but enzymatic levels.
Eduardo Castaño of the University of Buenos Aires, Argentina, together with colleagues at New York University and Sun Health Institute, Sun City, Arizona, compared IDE levels in AD-CAA patients with those in normal controls. They found that the amount of IDE was significantly elevated in the six AD-CAA cases (241.2 +/- 19 ng/mg, vs. 167.1 +/-24 ng/mg; p=0.04). At first glance this seemed to debunk the IDE/Aβ theory, but when the authors measured insulin degradation, they found it was threefold lower in AD-CAA cases than in controls.
The authors suggest the possibility that IDE is upregulated in the microvasculature in response to increases in Aβ, but this increase is more than overcome by IDE inhibitors. There are indications, for example, that protease inhibitors such as α1-antichymotrypsin, cystatin C, the Kunitz-type domain of AβPP, and anti-thrombin III are upregulated in AD brain. The authors also mention plasminogen activator inhibitor-1 and still uncharacterized heat-resistant, low-molecular-weight inhibitors that regulate IDE in liver (ubiquitin being one suspect). "Although the presence of IDE inhibitors in the brain and its microvasculature has not been described, our results raise the possibility that in CAA microvessels IDE is inhibited or inactivated, leading to a defective Aβ degradation that may be pathogenically relevant in dementia or stroke," the authors conclude.—Hakon Heimer.
Morelli L, Llovera RE, Mathov I, Lue LF, Frangione B, Ghiso J, Castano EM. Insulin degrading enzyme in brain microvessels: proteolysis of amyloid beta vasculotropic variants and reduced activity in cerebral amyloid angiopathy. J Biol Chem. 2004 Oct 15 [Epub ahead of print] Abstract