HNE-modified proteins in Down syndrome: Involvement in development of Alzheimer disease neuropathology

Eugenio Barone, Elizabeth Head, D. Allan Butterfield, Marzia Perluigi

Research output: Contribution to journalReview articlepeer-review

38 Scopus citations

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.

Original languageEnglish
Pages (from-to)262-269
Number of pages8
JournalFree Radical Biology and Medicine
Volume111
DOIs
StatePublished - Oct 2017

Bibliographical note

Publisher Copyright:
© 2017 Elsevier Inc.

Funding

FundersFunder number
NIH National Institute of Child Health and Human Development National Center for Medical Rehabilitation Research
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentR01HD064993
Eunice Kennedy Shriver National Institute of Child Health and Human Development

    Keywords

    • 4-hydroxy-2-nonenal
    • Alzheimer disease
    • Down syndrome
    • Lipid peroxidation
    • Protein oxidation
    • Redox proteomics

    ASJC Scopus subject areas

    • Biochemistry
    • Physiology (medical)

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