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

Topic: Brain proteins, microglia and lab models

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.

@article{barone2017-27838436,
  author  = {Barone, E. and Head, E. and Butterfield, D. A. and Perluigi, M.},
  title   = {{HNE-modified proteins in Down syndrome: Involvement in development of Alzheimer disease neuropathology}},
  journal = {Free radical biology \& medicine},
  year    = {2017},
  doi     = {10.1016/j.freeradbiomed.2016.10.508},
  pmid    = {27838436},
  url     = {https://doi.org/10.1016/j.freeradbiomed.2016.10.508}
}

Key findings

• 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.
• 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.

Why it matters

People with Down syndrome develop the same brain plaques and tangles seen in Alzheimer's, and this review argues that oxidative damage is part of the reason. It proposes that a fat-breakdown by-product called HNE sticks to brain proteins in Down syndrome and disrupts glucose use, transport inside nerve cells, protein clean-up and antioxidant defences. The authors present this as a hypothesis drawn from earlier studies; the review reports no new data and tests no treatment.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1016/j.freeradbiomed.2016.10.508
• PubMed: 27838436
• Original source →
• Free full text: UKnowledge (University of Kentucky) →

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Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 23.

• Diabetes mellitus and the risk of dementia: The Rotterdam Study Neurology · 1999-12-01 · usefulness score 72/100 · How common it is
• Glucose levels and risk of dementia The New England journal of medicine · 2013-08-01 · usefulness score 67/100 · Prevention and risk
• Association of Insulin Resistance With Cerebral Glucose Uptake in Late Middle-Aged Adults at Risk for Alzheimer Disease JAMA neurology · 2015-09-01 · usefulness score 63/100 · Brain tissue and pathology
• Hearing Loss and Cognitive Decline in Older Adults JAMA Internal Medicine · 2013-01-21 · usefulness score 57/100 · Risk factors
• Sequence of cognitive decline in dementia in adults with Down's syndrome Journal of intellectual disability research : JIDR · 2000-12-01 · usefulness score 54/100 · Down syndrome and Alzheimer's
• Amyloid β-peptide (1-42)-induced oxidative stress in Alzheimer disease: importance in disease pathogenesis and progression Antioxidants & redox signaling · 2013-02-14 · usefulness score 48/100 · Risk genes beyond APOE
• Biomarkers of oxidative stress are significantly elevated in Down syndrome Free radical biology & medicine · 1998-12-01 · usefulness score 47/100 · Down syndrome and Alzheimer's
• In vivo oxidative stress in brain of Alzheimer disease transgenic mice: Requirement for methionine 35 in amyloid beta-peptide of APP Free radical biology & medicine · 2009-10-23 · usefulness score 47/100 · Risk genes beyond APOE
• Association between frontal cortex oxidative damage and beta-amyloid as a function of age in Down syndrome Biochimica et biophysica acta · 2011-10-08 · usefulness score 47/100 · Down syndrome and Alzheimer's
• Life-long overexpression of S100beta in Down's syndrome: implications for Alzheimer pathogenesis Neurobiology of aging · 1998-09-01 · usefulness score 46/100 · Risk genes beyond APOE
• Redox proteomic identification of 4-hydroxy-2-nonenal-modified brain proteins in amnestic mild cognitive impairment: insight into the role of lipid peroxidation in the progression and pathogenesis of Alzheimer's disease Neurobiology of disease · 2008-01-05 · usefulness score 46/100 · Mild cognitive impairment
• Oxidative Stress and Down Syndrome: A Route toward Alzheimer-Like Dementia Current gerontology and geriatrics research · 2011-11-29 · usefulness score 46/100 · Down syndrome and Alzheimer's

Later studies that cite this one

9 studies in the alzhub library list this one in their references. Showing the 8 highest-scoring.

• Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease Nature reviews. Neuroscience · 2019-03-01 · usefulness score 57/100 · Mild cognitive impairment
• Oxidative Stress, Amyloid-β Peptide, and Altered Key Molecular Pathways in the Pathogenesis and Progression of Alzheimer's Disease Journal of Alzheimer's disease : JAD · 2018-01-01 · usefulness score 50/100 · Mild cognitive impairment
• Intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome Translational neurodegeneration · 2018-11-06 · usefulness score 47/100 · Down syndrome and Alzheimer's
• Brain insulin resistance triggers early onset Alzheimer disease in Down syndrome Neurobiology of disease · 2020-01-24 · usefulness score 45/100 · Down syndrome and Alzheimer's
• Restoration of aberrant mTOR signaling by intranasal rapamycin reduces oxidative damage: Focus on HNE-modified proteins in a mouse model of down syndrome Redox biology · 2019-03-09 · usefulness score 45/100 · Down syndrome and Alzheimer's
• The BACH1/Nrf2 Axis in Brain in Down Syndrome and Transition to Alzheimer Disease-Like Neuropathology and Dementia Antioxidants (Basel, Switzerland) · 2020-08-21 · usefulness score 43/100 · Down syndrome and Alzheimer's
• Disturbance of redox homeostasis in Down Syndrome: Role of iron dysmetabolism Free radical biology & medicine · 2017-07-10 · usefulness score 42/100 · Down syndrome and Alzheimer's
• Loss of Proteostasis and Early-Onset Neurodegeneration in Down Syndrome: From Mechanisms to Interventions Antioxidants (Basel, Switzerland) · 2026-04-21 · usefulness score 39/100 · Down syndrome and Alzheimer's

Related studies in Down syndrome and Alzheimer's

• Redox proteomics analysis of HNE-modified proteins in Down syndrome brain: clues for understanding the development of Alzheimer disease Free radical biology & medicine · 2014-03-25 · usefulness score 43/100
• Polyubiquitinylation Profile in Down Syndrome Brain Before and After the Development of Alzheimer Neuropathology Antioxidants & redox signaling · 2016-10-26 · usefulness score 43/100
• Possible compensatory events in adult Down syndrome brain prior to the development of Alzheimer disease neuropathology: targets for nonpharmacological intervention Journal of Alzheimer's disease : JAD · 2007-03-01 · usefulness score 41/100
• An investigation of the molecular mechanisms engaged before and after the development of Alzheimer disease neuropathology in Down syndrome: a proteomics approach Free radical biology & medicine · 2014-08-20 · usefulness score 39/100
• Impairment of proteostasis network in Down syndrome prior to the development of Alzheimer's disease neuropathology: redox proteomics analysis of human brain Biochimica et biophysica acta · 2013-04-18 · usefulness score 36/100
• Brain insulin resistance in Down syndrome: Involvement of PI3K-Akt/mTOR axis in early-onset of Alzheimer's disease and its potential as a therapeutic target Biochemical and biophysical research communications · 2024-09-17 · usefulness score 35/100

Also tagged “down”

527 studies in the library carry the topic tag “down”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 527 tagged studies.

• Link between DYRK1A overexpression and several-fold enhancement of neurofibrillary degeneration with 3-repeat tau protein in Down syndrome Journal of neuropathology and experimental neurology · 2011-01-01 · usefulness score 43/100 · Down syndrome and Alzheimer's
• Balance and Gait: Associations With Cognitive Impairment and Dementia in Individuals With Down Syndrome Alzheimer disease and associated disorders · 2023-10-02 · usefulness score 39/100 · Down syndrome and Alzheimer's
• Clinical and biomarker changes of Alzheimer's disease in adults with Down syndrome: a cross-sectional study The Lancet · 2020-06-01 · usefulness score 59/100 · Down syndrome and Alzheimer's

Similar studies

• Quantification of modified amyloid beta peptides in Alzheimer disease and Down syndrome brains 1998 · Down syndrome and Alzheimer's
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• Molecular abnormalities of the brain in Down syndrome: relevance to Alzheimer's neurodegeneration 1999 · Down syndrome and Alzheimer's
• Aging in Down Syndrome and the Development of Alzheimer's Disease Neuropathology 2016 · Inflammation and the immune system
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• A review that covers this ground mTOR in Down syndrome: Role in Aß and tau neuropathology and transition to Alzheimer disease-like dementia Free radical biology & medicine · 2017-08-12 · usefulness score 45/100
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