Impaired transcription in Alzheimer's disease: key role in mitochondrial dysfunction and oxidative stress

Alzheimer's disease (AD) is the major cause of dementia in the world. Abnormal extracellular accumulation of amyloid-β (Aβ) peptide and tau hyperphosphorylation, forming neurofibrillary tangles in the brain, are hallmarks of the disease. Oxidative stress, neuroinflammation, and mitochondrial and synaptic dysfunction are also observed in AD and often correlated to intracellular Aβ. This peptide results from the cleavage of the amyloid-β protein precursor by β- and γ-secretases and tends to be secreted after its production. However, secreted Aβ can be internalized by the interaction with membrane receptors, namely N-methyl-D-aspartate receptors, advanced glycation end products receptors, and/or alpha 7 nicotinic acetylcholine receptors. Inside the cell, Aβ interacts with several organelles, including mitochondria and nucleus, and there is growing evidence pointing to a possible role of Aβ in the regulation of gene transcription. Accordingly, transcriptional deregulation was observed in several AD models and human samples from AD patients through modified expression, phosphorylation levels, function, and subcellular localization of some transcription factors, resulting in the suppression of neuroprotective transcription both in the nucleus and the mitochondria. In this review we focus on key transcription regulators related with mitochondrial biogenesis and antioxidant defenses that seem to be altered in AD models and also on the role of intranuclear Aβ in the pathogenesis of the disease.