Medical News Observer

Key Points:

• Mitochondrial dysfunction has been identified as a contributor to synaptic degradation in Alzheimer’s disease.
• Research uncovers a specific blockage in neurons’ energy cycle caused by faulty protein activity, highlighting a target for intervention.
• Experimental treatment with a succinate analog significantly recovers synaptic connections in Alzheimer’s neuron models.

Overview

In a recent study focusing on Alzheimer’s disease, researchers from Scripps Institute investigated the link between dysfunctional mitochondrial metabolism and synaptic loss, a critical factor in cognitive decline. Using neuron models, they discovered that in Alzheimer’s, energy production within brain cells is impaired, specifically in the mitochondria. This leads to the disconnection and degeneration of synapses, crucial for memory retention and formation. 

Mitochondrial dysfunction in Alzheimer’s disease

The study delved deeper into the underlying causes of the energy production failure using human induced pluripotent stem cell (hiPSC)-derived cerebrocortical neurons (hiN), wild-type and with Alzheimer’s disease mutations. The researchers discovered a significant block in the tricarboxylic acid (TCA) cycle at the α-ketoglutarate dehydrogenase (αKGDH)/succinyl coenzyme-A synthetase step. They found that aberrant protein S-nitrosylation of αKGDH subunits impaired their enzyme function, a phenomenon also observed in postmortem human Alzheimer’s disease brains.

By supplying an analog of succinate, the team could jumpstart the stalled Krebs cycle, repairing up to three-quarters of the lost synapses and preventing further decline. They partially restored mitochondrial bioenergetic function and reversed synapse loss in the Alzheimer’s disease neuron models. 

Implications

This breakthrough underscores the potential of improving mitochondrial metabolism as a therapeutic approach for Alzheimer’s and related disorders. While not immediately leading to treatment, this study offers a new direction for developing effective drugs to restore neuronal connectivity and halt Alzheimer’s progression.

Reference

Andreyev, Alexander Y., Hongmei Yang, Paschalis-Thomas Doulias, Nima Dolatabadi, Xu Zhang, Melissa Luevanos, Mayra Blanco, et al. n.d. “Metabolic Bypass Rescues Aberrant S-Nitrosylation-Induced TCA Cycle Inhibition and Synapse Loss in Alzheimer’s Disease Human Neurons.” Advanced Science n/a (n/a): 2306469. https://doi.org/10.1002/advs.202306469.