br Transparency document br Acknowledgements The authors
Acknowledgements The authors gratefully acknowledge the National Institute on Minority Health and Health Disparities (G12MD007591).
Introduction Alzheimer's disease (AD) is the leading cause of dementia in the elderly population, affecting approximately 40 million people worldwide [1,2]. This neurodegenerative disease is the result of progressive neurodegenerative changes in the human brain, which lead to a progressive decline in memory, language and attention . From a neuropathological point of view, the AD Filipin Complex inhibitor exhibits the presence of two distinctive pathological hallmarks: the extracellular deposition of amyloid-β (Aβ) peptide in senile plaques and the intracellular accumulation of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein . Additional features include microgliosis and a widespread and progressive loss of neurons, synapses and white matter [1,5]. Cognitive and behavioral symptoms constitute only the “tip of the iceberg”, since the disruption of brain structure and function and consequent neuronal loss precede the clinical signs of the disease by 20–30 years . Within this scenario, defective cerebral metabolism has gained attention as a possible initial cause of this neurodegenerative disease, particularly for the sporadic cases of AD, where aging and metabolic disorders are main risk factors [7,8]. In fact, compelling evidence revealed that regional brain hypometabolism occurs prior to the occurrence of senile plaques and NFTs in both genetic and sporadic AD [, , , , , ] suggesting impaired glucose metabolism may be an upstream event in AD progression. The nutrient-sensing pathway that encompasses the dynamic and reversible post-translational modification called O-linked-β-N-acetylglucosaminylation (O-GlcNAcylation) plays a significant role in disease progression. In fact, O-GlcNAcylation of nuclear, cytoplasmic and mitochondrial target proteins is proposed to act as a metabolic sensor that links glucose metabolism to neuronal function. In a process that resembles phosphorylation , O-GlcNAc, derived from the final product of the nutrient-dependent hexosamine biosynthetic pathway (HBP), is added to or removed from hydroxyl groups of serine and/or threonine residues by two highly conserved intracellular enzymes, O-GlcNAc transferase (OGT) and O-linked-β-N-acetylglucosaminidase (OGA), respectively [16,17]. Recent breakthroughs revealed that the forebrain-specific loss of OGT in adult mice leads to progressive neurodegeneration, accumulation of protein aggregates and memory deficits . Moreover, amyloid precursor protein (APP) and tau protein, as well as several proteins involved in regulatory cascades that mediate intracellular signaling, were shown to be heavily modified by O-GlcNAc . During synaptic activity O-GlcNAcylation also regulates mitochondrial trafficking by targeting the mitochondrial motor-adaptor Milton, which is responsible for tethering mitochondria to motor proteins allowing the movement of these organelles along the microtubule tracks . However, so far, there is no consensus regarding the exact participation of O-GlcNAcylation in AD with conflicting data reporting both augmented and diminished O-GlcNAcylation levels in this neurodegenerative disease. Furthermore, the exact mechanism responsible for altered O-GlcNAcylation in AD brain remains inconclusive. Taking into account that AD-related glucose hypometabolism is accompanied by an abnormal mitochondrial function and distribution within neurons, which ultimately culminates in synaptic “starvation” and neuronal degeneration, and that O-GlcNAcylation was shown to modulate mitochondrial function, motility and distribution, the present study was undertaken to clarify the involvement O-GlcNAcylation in AD mitochondrial pathology.
Materials and methods