Mitochondrial Dysfunction Contributes to the Pathogenesis of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease that affects millions of people worldwide. Currently, there is no effective treatment for AD, which indicates the necessity to understand the pathogenic mechanism of this disorder. Extracellular aggregates of amyloid precursor protein (APP), called Aβ peptide and neurofibrillary tangles (NFTs), formed by tau protein in the hyperphosphorylated form are considered the hallmarks of AD. Accumulative evidence suggests that tau pathology and Aβ affect neuronal cells compromising energy supply, antioxidant response, and synaptic activity. In this context, it has been showed that mitochondrial function could be affected by the presence of tau pathology and Aβ in AD. Mitochondria are essential for brain cells function and the improvement of mitochondrial activity contributes to preventing neurodegeneration. Several reports have suggested that mitochondria could be affected in terms of morphology, bioenergetics, and transport in AD. These defects affect mitochondrial health, which later will contribute to the pathogenesis of AD. In this review, we will discuss evidence that supports the importance of mitochondrial injury in the pathogenesis of AD and how studying these mechanisms could lead us to suggest new targets for diagnostic and therapeutic intervention against neurodegeneration.

Figure 1

Mitochondrial dysfunction in AD. Factors that contributed to AD such as injury, aging, and inflammation can affect three critical aspects of mitochondrial function: (1) mitochondrial dynamics (inducing fragmentation), (2) bioenergetics (ATP and ROS production), and (3) mitochondrial movement (synaptic function). ATP: adenosine triphosphate; ΔΨ: mitochondrial membrane potential; ROS: reactive oxygen species.

Figure 2

Improving mitochondrial health in AD. In AD, the action of tau and Aβ generates impairment of the mitochondrial function causing fragmentation, depolarization, oxidative stress, and defects in axonal transport. Several strategies have been used to reduce mitochondrial failure in AD. These elements include antioxidants (systemic and mitochondria-targeted), inhibitors of mitochondrial dynamics, microtubules stabilizing drugs, and increase of mitochondrial biogenesis. Also, in this review, we propose the use of a “double mitochondrial therapy,” which means the combinatory use of mitotargeted antioxidants and activators of mitochondrial biogenesis. The use of these therapies can potentially reduce the mitochondrial fragmentation improving the mitochondrial network, restore the membrane potential (increasing ATP production and reducing ROS levels), and increase axonal transport. ΔΨ: mitochondrial membrane potential; VDAC1: voltage-dependent anion channel; HDAC6: histone deacetylase 6; Nrf2: nuclear factor erythroid 2-related factor 2; PGC1-α: peroxisome proliferator-activated receptor gamma-coactivator 1 alpha.