Dihydrolipoamide dehydrogenase (DLD) as a potential therapeutic target for Alzheimer’s disease — ASN Events

Dihydrolipoamide dehydrogenase (DLD) as a potential therapeutic target for Alzheimer’s disease (#53)

Waqar Ahmad 1 , Paul R Ebert 1
  1. The University of Queensland, St Lucia, QLD, Australia

Altered energy metabolism is associated with Alzheimer’s disease (AD) and is proposed to influence disease progression. Amyloid beta (Aβ) plaque formation, a major contributor to AD pathology as well as a marker of disease progression is frequently concurrent with distorted brain metabolism. Unfortunately in AD pathogenesis, it is still difficult to distinguish cause from consequence. For example, the decrease in energy metabolism associated with AD may be interpreted either as a consequence of, or response to, factors associated with the disease such as elevated levels of oxidative stress. Dihydrolipoamide dehydrogenase (DLD) is a core metabolic enzyme associated with four important mitochondrial enzyme complexes. Interestingly, dld gene variants are genetically linked to late-onset Alzheimer’s disease (AD); and reduced activity of DLD-containing enzyme complexes has been observed in AD patients. To understand how energy metabolism influences AD progression, we suppressed the dld-1 genein worms expressing the human Aβ peptide and also decreased the activity of the DLD enzyme by exposure to the chemical inhibitor, 2-methoxyindole-5-carboxylic acid (MICA). As previously reported, we see that expression of human Aβ in the worm model of AD is associated with decreased lifespan, enhanced paralysis, reduced acetylcholine neurotransmission, hypersensitivity to serotonin, perturbation of chemotaxis and increased Aβ oligomerization. Suppression of either the dld-1 gene or the activity of its encoded enzyme not only increased lifespan but also alleviated the symptoms associated with expression of human Aβ. Suppression of the dld-1 gene also results in a decrease in the abundance of toxic Aβ oligomers. These protective effects of dld-1 suppression seem to be associated with calcium homeostasis as they could be reversed by exposure to a calcium ionophore.

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