What’s new?
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In a forthcoming article in ACS Chemical Neuroscience, we show that Aß(pyroE3-42), the most neurotoxic form of Aß, inhibits the IDE*-dependent degradation of Aß(1-40) and insulin. This work provides a mechanism for the loss of IDE activity that has been associated with aging and Alzheimer’s disease. (*insulin-degrading enzyme)
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In Neuroscience 2022, we presented a poster showing differential susceptibilities of ApoE* isoforms (ApoE2, ApoE3, and ApoE4) to proteolytic degradation by human neutrophil elastase. ApoE4, the major genetic risk factor for sporadic Alzheimer’s disease, is significantly more susceptible to proteolytic degradation than ApoE2 and ApoE3. This work suggests that ApoE proteostasis in people who only produce ApoE4 is impaired. (*Apolipoprotein E, the major transporter of lipids in the brain)
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Amy Zheng et al. (ACS Omega 2022) demonstrated that anionic lipids in membranes increase the levels of IDE-degradable insulin monomer. This finding, however, does not apply to the other substrates of IDE in that the aggregation of IDE’s amyloidogenic substrates (e.g., Aß(1-40) and Aß(1-42)) is enhanced by anionic lipids. The differential effects of anionic lipids in modulating the levels of the monomeric states of insulin and Aß suggest that the lipid composition of membranes is an important determinant of IDE’s ability to regulate the levels of its physiologically and pathologically relevant substrates.
