How Aβ Peptides Modulate Insulin Degradation in Alzheimer’s Disease and Diabetes

Insulin-degrading enzyme (IDE), a ubiquitous zinc metalloprotease, is integral to the degradation of insulin and amyloidogenic substrates, which have been implicated in various late-onset disorders including Alzheimer’s disease (AD) and type 2 diabetes (T2D). In T2D, IDE is involved in the breakdown of insulin, which has a direct impact on insulin levels and activity in the body. Abnormalities in IDE function can lead to altered insulin levels, contributing to insulin resistance, a hallmark of T2D. Therefore, maintaining a balance in IDE activity is crucial for proper insulin regulation. On the other hand, in AD, IDE is known to degrade amyloid-beta (Aβ) peptides. A reduction in IDE activity can also contribute to the accumulation of these peptides, exacerbating AD pathology. Additionally, there is a link between insulin signaling and brain health, further connecting IDE’s role in both AD and T2D. Thus, understanding IDE’s mechanisms could provide insights into the development of therapeutic strategies for these conditions.

A new study published in ACS Chemical Neuroscience by Merc Kemeh and Professor Noel Lazo from the Carlson School of Chemistry and Biochemistry at Clark University, investigated IDE’s ability to degrade insulin in the presence of two different Aβ peptides: Aβ(1-40), the most abundant Ab peptide in the normal brain, and Aβ(pyroE3-42), the most pathogenic form of Ab in AD. Traditionally, studies focused on IDE’s activity with a single substrate. However, this research posits a more realistic scenario where IDE encounters multiple substrates in the brain’s complex environment. The authors employed enzyme kinetics using Circular Dichroism Spectroscopy, which is based on monitoring the helical circular dichroic signal of insulin as its proteolytic degradation proceeds. They also employed Matrix Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry to identify the specific fragments generated during the enzymatic digestion. The study uncovers that Aβ peptides modulate IDE’s activity towards insulin in contrasting ways.  While Aβ(1−40) enhances IDE’s insulin degradation capacity,  Aβ(pyroE3−42) inhibits it. This modulation offers a deeper understanding of the  molecular mechanisms driving AD pathology and insulin dysregulation in the brain.

The researchers also demonstrated that IDE has varied efficiency in degrading different substrates. It is less efficient in degrading insulin due to its primarily α-helical structure, whereas it degrades Aβ(1−40) more rapidly, likely because of its β-sheet-like interactions with the enzyme. The inhibition of IDE by Aβ(pyroE3−42) could be due to inhibition of exosite-assisted unfolding of Aβ(pyroE3−42) by pyroglutamate formation in its N-terminus, leading to stable complex formation with IDE. This mechanism could explain the observed decrease in IDE activity and the accumulation of Aβ in AD. They highlighted that IDE’s function extends beyond simple insulin degradation; it is implicated in the regulation of Aβ levels in vivo. Interestingly, a decrease in IDE activity correlates with aging and the onset of AD, further cementing its critical role in neurodegenerative processes. In discussing the mechanistic implications of their work, the authors discussed the generally accepted structural aspects of IDE. The enzyme is a homodimer, each monomer composed of N-terminal and C-terminal domains linked by a flexible loop. This structure forms a catalytic chamber, crucial for its enzymatic activity. The synchronized motion between IDE’s two conformational states – open for substrate capture and release, and closed for catalysis – is fundamental to understanding IDE’s ability to degrade its substrates, particularly insulin and Aβ peptides.

The new study has profound implications for understanding the pathophysiology of AD and T2D. The stable complex formation between Aβ(pyroE3−42) and IDE locks the enzyme in a closed state, leading to its inactivation. This could explain the accumulation of Aβ in the brain, a hallmark of AD. Moreover, the modulation of insulin degradation by Aβ peptides provides a link to insulin signaling dysfunction, a factor implicated in both AD and T2D. The revelations from this study warrant further research into IDE as a therapeutic target. Understanding the nuances of IDE’s interaction with various Aβ peptides could guide the development of drugs aimed at modulating IDE activity. The inhibition of IDE by Aβ(pyroE3−42) opens a new therapeutic window for targeting specific Aβ forms in AD. Additionally, the study’s methodology, blending kinetic assays with advanced spectroscopy, sets a precedent for future biochemical research in this domain. In conclusion, the findings of Kemeh and Lazo have significant implications for understanding the pathological processes in AD and T2D, particularly in how insulin signaling and Aβ peptide accumulation are regulated in the brain. In essence, the study provided crucial insights into the biochemical dynamics of IDE in the presence of various substrates, underscoring the complexity of enzyme-substrate interactions in neurodegenerative diseases.