title: HNE-modified proteins in Down syndrome: Involvement in development of Alzheimer disease neuropathology.
abstract: Down syndrome (DS), trisomy of chromosome 21, is the most common genetic form of intellectual disability. The neuropathology of DS involves multiple molecular mechanisms, similar to AD, including the deposition of beta-amyloid (Aβ) into senile plaques and tau hyperphosphorylationg in neurofibrillary tangles. Interestingly, many genes encoded by chromosome 21, in addition to being primarily linked to amyloid-beta peptide (Aβ) pathology, are responsible for increased oxidative stress (OS) conditions that also result as a consequence of reduced antioxidant system efficiency. However, redox homeostasis is disturbed by overproduction of Aβ, which accumulates into plaques across the lifespan in DS as well as in AD, thus generating a vicious cycle that amplifies OS-induced intracellular changes. The present review describes the current literature that demonstrates the accumulation of oxidative damage in DS with a focus on the lipid peroxidation by-product, 4-hydroxy-2-nonenal (HNE). HNE reacts with proteins and can irreversibly impair their functions. We suggest that among different post-translational modifications, HNE-adducts on proteins accumulate in DS brain and play a crucial role in causing the impairment of glucose metabolism, neuronal trafficking, protein quality control and antioxidant response. We hypothesize that dysfunction of these specific pathways contribute to accelerated neurodegeneration associated with AD neuropathology.
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, Italy; Universidad Autónoma de Chile, Instituto de Ciencias Biomédicas, Facultad de Salud, Avenida Pedro de Valdivia 425, Providencia, Santiago, Chile.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Barone
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA; Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Head
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA; Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, Italy. Electronic address: marzia.perluigi@uniroma1.it.
authors.forename: Marzia
authors.initials: M
authors.lastname: Perluigi
mesh_terms: D000447:Aldehydes / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011499:Protein Processing, Post-Translational; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000447:Aldehydes; D016229:Amyloid beta-Peptides; C054369:MAPT protein, human; D016875:tau Proteins; D005947:Glucose; C027576:4-hydroxy-2-nonenal
keywords: 4-hydroxy-2-nonenal; Alzheimer disease; Down syndrome; Lipid peroxidation; Protein oxidation; Redox proteomics