Mitochondrial Dysfunction in Alzheimer’s: Insights for New Therapies - European Medical Journal

Mitochondrial Dysfunction in Alzheimer’s: Insights for New Therapies

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A HIGHLY TOXIC protein, oligomeric amyloid-beta (OAβ), has been shown to disrupt mitochondria, contributing to and potentially driving the progression of Alzheimer’s disease (AD). Previously, drugs targeting amyloid-beta to treat AD have shown disappointing results. Now, researchers from Arizona State University, Tempe, Arizona, USA, have presented new evidence proposing that Oaβ accelerates natural mitochondrial decline; consequently, pre-treating mitochondria may offer an exciting, novel avenue for AD treatment.

AD is an extremely debilitating and often fatal neurogenerative disorder affecting millions worldwide. Known hallmarks include amyloid-beta protein accumulation and tissue destruction in the hippocampus and neocortex, areas key to learning, memory, and cognition. However, as amyloid-beta targeted drugs have proved unsuccessful, researchers have argued amyloid-beta accumulation must occur in later stages and other triggers must exist. This in addition to observed deficiencies in energy metabolism during early AD pathobiology, has led to research to focus on the early role that mitochondria play.

Neurodegenerative diseases are known to selectively target and destroy hippocampal pyramidal neurons. Therefore, researchers, led by Dr Diego Mastroeni , Arizona State University, extracted hippocampal neurons from the brains of AD patients during the post-mortem and found reduced expression of many mitochondrial genes, presenting strong evidence that OAβ causes injurious effects on the mitochondria. This reduction in mitochondrial gene expression was also present when cells from a human neuroblastoma cell line were exposed to OAβ.

Further to this, other nervous system cells, such as astrocytes and microglia primarily involved in supportive and immunological functions, were found not to be affected by mitochondrial dysfunction caused by OAβ exposure. Therefore, the team concluded that mitochondrial disruption due to OAβ was specific to pyramidal neurons.

In subsequent experiments, human neurons were pretreated in vitro with an analogue of coenzyme Q10, a compound adept at boosting ATP production while limiting oxidative stress prior to exposure to OAβ. Interestingly, it was found that the synthesised compound protected neurons from degradation, combatting the effects of OAβ-induced mitochondrial dysfunction. With these new discoveries suggesting a new exciting avenue for future drug targeting, Dr Mastroeni explained: “This study reinforces the toxicity of oligomeric amyloid-beta  on neuronal mitochondria and stresses the importance for protective compounds to protect the mitochondria from oligomeric amyloid-beta toxicity.”

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