Exploring the therapeutic potential of mitochondrial uncouplers in the context of Alzheimer´s disease

Overview

Project Summary

Since its first description, Alzheimer´s disease (AD) has gone from a rarely reported disorder to one of the most common disabling diseases among older adults. AD is characterized by two pathological hallmarks, the extracellular deposition of amyloid-β peptide in senile plaques and the intracellular accumulation of neurofibrillary tangles composed by hyperphosphorylated tau protein, which are accompanied by a dramatic synaptic and neuronal loss. AD neuropathology is also characterized by hypo metabolism, impaired mitochondrial bioenergetics, oxidative stress and neuroinflammation. However, despite the global attention, AD treatment remains an unsolved issue. An inherent part of mitochondrial physiology relates with the uncoupling of respiration from oxidative phosphorylation. In the brain, this process is intrinsically mediated by three specific mitochondrial uncoupling proteins, UCP2, UCP4 and UCP5. UCPs and chemical uncouplers are known to lessen the proton motive force across the mitochondrial inner membrane and thereby increase the rate of mitochondrial respiration while decreasing the production of reactive oxygen species (ROS). Among the different mitochondrial uncouplers, 2,4 Dinitrophenol (DNP), BAM15 and niclosamide ethanolamine (NEN) have emerged as promising compounds able to harness several diseases. However, as far as we know, their therapeutic potential in AD remains largely unexplored. Our preliminary work demonstrates that a low concentration of DNP can revert okadaic acid-induced AD-like pathological changes in neuron-like differentiated SH-SY5Y cells. These preliminary observations, and the existing literature, undergird our working hypothesis, which postulates that mitochondrial uncouplers, by directly targeting mitochondria, may play an important role in mitigating AD pathophysiology.

Main Goals

To present robust preclinical experimental evidence that the direct modulation of mitochondria by mitochondrial uncouplers can be a useful tool to protect brain cells from the irreversible pathological events that occur in AD pathology.

Project Details