Mitochondrial Dysfunction in the Pathophysiology of Alzheimer’s Disease

Mitochondria are responsible for the majority of energy production in the brain, modulate Ca⁺² signaling and control initiation of cell death. Because of their extensive use of oxygen and lack of protective histone proteins, mitochondria are particularly vulnerable to oxidative stress (ROS)-induced damage to their genome (mtDNA), respiratory chain proteins and ROS repair enzymes. Maintenance of mitochondrial mass, mitochondrial biogenesis (mitobiogenesis), particularly in high-energy utilizing brain, occurs through complex signaling pathways involving the upstream “master regulator” PGC-1α which is transcriptionally and post-translationally regulated.

Alzheimer’s disease (AD) brains have reduced respiratory capacity and impaired mitobiogenesis, which could result in beta-amyloid (Aβ) plaques and neurofibrillary tangles. Aggregated proteins in familial AD brains impair mitochondrial function, and mitochondrial dysfunction is involved in activated neuroinflammation. Mitochondrial ROS can activate signaling pathways that mediate neurodegeneration. Available data support restoration of mitochondrial function to reduce disease progression and restore lost neuronal function in AD.