Communication breaks-Down: From neurodevelopment defects to cognitive disabilities in Down syndrome

Contestabile, Andrea; Benfenati, Fabio; Gasparini, Laura

doi:10.1016/j.pneurobio.2010.01.003

Cited by 134Down syndrome and intellectual disability researchAlzheimer's disease research and treatmentsGenetics and Neurodevelopmental Disorders

Communication breaks-Down: From neurodevelopment defects to cognitive disabilities in Down syndrome

Contestabile, Andrea, Benfenati, Fabio, Gasparini, Laura·2010·Progress in Neurobiology

DOI 10.1016/j.pneurobio.2010.01.003

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Abstract

Down syndrome (DS) is the leading cause of genetically-defined intellectual disability and congenital birth defects. Despite being one of the first genetic diseases identified, only recently, thanks to the phenotypic analysis of DS mouse genetic models, we have begun to understand how trisomy may impact cognitive function. Cognitive disabilities in DS appear to result mainly from two pathological processes: neurogenesis impairment and Alzheimer-like degeneration. In DS brain, suboptimal network architecture and altered synaptic communication arising from neurodevelopmental impairment are key determinants of cognitive defects. Hypocellularity and hypoplasia start at early developmental stages and likely depend upon impaired proliferation of neuronal precursors, resulting in reduction of numbers of neurons and synaptic contacts. The impairment of neuronal precursor proliferation extends to adult neurogenesis and may affect learning and memory. Neurodegenerative mechanisms also contribute to DS cognitive impairment. Early onset Alzheimer disease occurs with extremely high incidence in DS patients and is causally-related to overexpression of beta-amyloid precursor protein (betaAPP), which is one of the triplicated genes in DS. In this review, we will survey the available findings on neurodevelopmental and neurodegenerative changes occurring in DS throughout life. Moreover, we will discuss the potential mechanisms by which defects in neurogenesis and neurodegenerative processes lead to altered formation of neural circuits and impair cognitive function, in connection with findings on pharmacological treatments of potential benefit for DS.

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In Down syndrome, cognitive abilities are affected due to a developmental delay including the maturation of brain areas such as the PFC.
“Cognitive abilities are affected due to a developmental delay including the maturation of brain areas such as the PFC [293].”
From Development of prefrontal cortex (2022) · cites this paper as [293]

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Development of prefrontal cortex
Kolk, S. M., & Rakic, P. (2022) · Neuropsychopharmacology · doi:10.1038/s41386-021-01137-9 · Cited by 378 · see citing works
“Cognitive abilities are affected due to a developmental delay including the maturation of brain areas such as the PFC [293].”
Background
An epigenetic framework for neurodevelopmental disorders: From pathogenesis to potential therapy
Millan, M. J. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.11.015 · Cited by 229 · see citing works
DYRK1A, a dosage-sensitive gene involved in neurodevelopmental disorders, is a target for drug development in down syndrome
Duchon, A., & Herault, Y. (2016) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2016.00104 · Cited by 181 · see citing works
Form and function of sleep spindles across the lifespan
Clawson, B. C., Durkin, J., & Aton, S. J. (2016) · Neural Plasticity · doi:10.1155/2016/6936381 · Cited by 178 · see citing works
“For example, childrenwithDown syndrome show decreased proliferation of neuronal progenitor cells during gestation, decreased mature neuronal numbers overall, decreased dendritic spine density, changes in LTP and LTD, and early-onset neurodegeneration when compared with typically developing children [129–131].”
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Targeting mTOR to reduce Alzheimer-related cognitive decline: from current hits to future therapies.
Tramutola, A., Lanzillotta, C., & Di Domenico, F. (2017) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2017.1244482 · Cited by 69 · see citing works

Demographic Characteristics, Health Conditions, and Residential Service Use in Adults with Down Syndrome in 25 U.S. States
Stancliffe, R. J., Lakin, K. C., Larson, S. A., et al. (2012) · Intellectual and developmental disabilities · doi:10.1352/1934-9556-50.2.92 · Cited by 70 · see citing works
Increased superoxide dismutase and Down’s syndrome
Turrens, J. F. (2001) · Medical Hypotheses · doi:10.1054/mehy.2001.1327 · Cited by 27 · see citing works
Abnormal Protein Profiles in Hippocampus of Mouse Models of Down Syndrome: Similarities with Alzheimers Disease
Dhanasekaran, A. R. (2014) · Journal of Alzheimer’s Disease & Parkinsonism · doi:10.4172/2161-0460.1000138 · Cited by 11 · see citing works
Pharmacological approaches to improving cognitive function in Down syndrome: current status and considerations
Gardiner, K. (2014) · Drug Design Development and Therapy · doi:10.2147/dddt.s51476 · Cited by 114 · see citing works
Down syndrome, Alzheimer's disease and the trisomy 16 mouse
Coyle, J. T., Oster‐Granite, M. L., REEVES, R., & Gearhart, J. P. (1988) · Trends in Neurosciences · doi:10.1016/0166-2236(88)90075-6 · Cited by 86 · see citing works

Authors: Contestabile, A., Benfenati, F., & Gasparini, L.
Affiliations: Italian Institute of Technology (IT)
Corresponding author: Contestabile, Andrea
Gasparini, Laura
ORCID: Contestabile, Andrea
Benfenati, Fabio
Gasparini, Laura
Venue: Progress in Neurobiology
Publisher: Elsevier BV
Published: 2010-05
Volume: 91
Issue: 1
Pages: 1-22
ISSN: 0301-0082 (ISSN-L)
DOI: 10.1016/j.pneurobio.2010.01.003
OpenAlex: W2084697692
Cited by: 134
References: 344
Citations by year: 2025: 6 · 2024: 6 · 2023: 5 · 2022: 5 · 2021: 12 · 2020: 9 · 2019: 6 · 2018: 3 · 2017: 7 · 2016: 13 · 2015: 12 · 2014: 15 · 2013: 8 · 2012: 8
FWCI: 1.61
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Progress in Neurobiology (publishedVersion)
PubMed (publishedVersion)
CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
Topics: Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords: Down syndrome, intellectual disability, neurodevelopmental impairment, neurogenesis, adult neurogenesis, neural progenitor proliferation, early-onset Alzheimer's disease, amyloid precursor protein, synaptic transmission, neural circuit formation, cognitive impairment, learning and memory, pharmacotherapy
MeSH terms: Animals, Brain, Chromosome Mapping, Cognition Disorders, Disease Models, Animal, Down Syndrome, Humans, Intellectual Disability, Trisomy, Neurogenesis

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Communication breaks-Down: From neurodevelopment defects to cognitive disabilities in Down syndrome

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