Researchers at the European Synchrotron, ESRF, have uncovered a surprising link between amyloid oligomers and mitochondrial energetics during the early stages of Alzheimer’s disease.
Unlike previous findings in advanced Alzheimer’s, amyloid oligomers appear to accelerate mitochondrial function in early stages.
This discovery could provide valuable insights into diagnosing and addressing Alzheimer’s in its early phases.
Alzheimer’s is an incurable neurodegenerative disease that typically manifests after the age of 65, but brain changes begin decades earlier.
Dysfunctional mitochondria, which produce cellular energy, may malfunction up to 20 years before Alzheimer’s symptoms emerge.
While researchers have traditionally focused on amyloid plaques as potential culprits, recent studies are exploring aging factors such as mitochondrial dysfunction.
Mitochondria and Alzheimer’s
Mitochondria are often called the “powerhouses of cells” because they generate energy. Over time, oxidative stress can impair mitochondria, leading to their malfunction.
Emerging evidence suggests that people with Alzheimer’s may accumulate amyloids within their mitochondria, challenging the previous belief that amyloids only exist outside neurons.
In the initial phases of Alzheimer’s, amyloids primarily exist as amyloid-beta oligomers before becoming fibrils. Researchers are now investigating what occurs within mitochondria during these early stages.
Complex I and Mitochondrial Function
Mitochondrial energy production relies on the respiratory chain, which includes five protein complexes working together. Complex I (CI) is a critical enzyme in this chain.
For CI to function correctly, assembly factors are essential, including the mitochondrial Complex I Assembly (MCIA) complex, consisting of ECSIT, ACAD9, and NDUFAF1 proteins.
Scientists used cryo-electron microscopy to determine the structure of the ACAD9-ECSIT complex. Understanding this structure is pivotal for unraveling the assembly mechanism.
The study revealed that ECSIT deactivates ACAD9’s fatty acid oxidizing function through a deflavination process. This redirects ACAD9 to its role in CI assembly, regulating cellular energy mechanisms. Moreover, dephosphorylation of ECSIT is crucial for the proper formation of MCIA.
Experimental results showed that amyloid-beta oligomers’ presence leads to ECSIT dephosphorylation in mitochondria.
This dephosphorylation enhances CI activity, contrary to previous findings indicating CI shutdown. This overactive CI, driven by amyloid oligomers, may disrupt the respiratory chain, potentially contributing to Alzheimer’s onset.
These findings shed light on amyloid-beta oligomers’ role during the early stages of Alzheimer’s. Understanding this role could open new avenues for diagnosing and addressing Alzheimer’s in its early phases.
While much research remains, this discovery offers hope for improved diagnosis and intervention.
If you care about dementia, please read studies about Early heart rhythm problem linked to higher dementia risk and findings that Green leafy vegetables may help reduce Alzheimer’s risk.
For more information about Alzheimer’s disease, please see recent studies about Foods that reduce Alzheimer’s risk and results showing that Scientists link dietary antioxidants to Alzheimer’s prevention.
The research findings can be found in Nature Communications.
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