by Researchers from the European Synchrotron (ESRF) have made a groundbreaking discovery regarding the early stages of Alzheimer’s disease. Contrary to previous findings, the study reveals that amyloid oligomers actually accelerate mitochondrial energetics during the initial phases of the disease. This new insight sheds light on the biology of Alzheimer’s and may pave the way for improved diagnosis and prevention strategies.
Alzheimer’s disease currently affects around 30 million people worldwide, but its exact origins remain unknown despite extensive research efforts. Understanding the factors that contribute to this neurodegenerative disease is crucial in developing effective treatments and measures to delay its onset and progression.
The team, led by Montse Soler López from the ESRF, focused on mitochondrial dysfunction as a key aging factor implicated in Alzheimer’s. Mitochondria are responsible for energy production in cells and are therefore often referred to as the “powerhouse” of cells. As mitochondria deteriorate over time, oxidative stress occurs, leading to their dysfunction.
Previous studies primarily examined the role of amyloid plaques in the brain as the main cause of Alzheimer’s. However, this new research challenges that hypothesis and explores the involvement of aging factors such as mitochondrial dysfunction.
The researchers found that individuals with Alzheimer’s may accumulate amyloids within mitochondria, contrary to previous belief that amyloids were only present outside neurons. The team specifically investigated the early stages of Alzheimer’s, where amyloids exist as amyloid-beta oligomers before transforming into fibrils.
Mitochondrial Complex I (CI), the largest and most critical enzyme involved in energy production, relies on assembly factors for optimal functionality. The scientists focused on the assembly factor complex known as mitochondrial Complex I Assembly (MCIA), which consists of three core proteins: ECSIT, ACAD9, and NDUFAF1.
Using cryo-electron microscopy, the team successfully determined the structure of the ACAD9-ECSIT complex, providing unprecedented insights into the assembly mechanism. They discovered that ECSIT deactivates the fatty acid oxidizing function of ACAD9, redirecting the protein to its role in assembling CI. This coordination and regulation of cellular energy mechanisms are crucial for proper mitochondrial function.
Furthermore, the researchers observed that dephosphorylation of ECSIT is necessary for the formation of MCIA. Interestingly, the presence of amyloid-beta oligomers in purified mitochondria led to increased dephosphorylation of ECSIT. This, in turn, resulted in an overactive CI and the formation of a stable dephosphorylated MCIA complex, essential for correct CI assembly.
These findings contradict previous studies that suggested CI shutdown in brain tissues from Alzheimer’s patients. Instead, the researchers observed an overactive CI in the early stages of the disease, indicating a detrimental cycle that ultimately impairs the respiratory chain.
Soler López highlights that these findings provide insight into the role of amyloid-beta oligomers at the onset of Alzheimer’s. By understanding these early events, new strategies for addressing the disease in its earliest stages can be explored, offering hope for improved diagnosis and treatment options. Further research is needed to fully understand the complex mechanisms involved in Alzheimer’s development and progression
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1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it
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