RGD Reference Report - Nerve growth factor metabolic dysfunction in Down's syndrome brains. - Rat Genome Database

Send us a Message



Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   

Nerve growth factor metabolic dysfunction in Down's syndrome brains.

Authors: Iulita, M Florencia  Do Carmo, Sonia  Ower, Alison K  Fortress, Ashley M  Flores Aguilar, Lisi  Hanna, Michael  Wisniewski, Thomas  Granholm, Ann-Charlotte  Buhusi, Mona  Busciglio, Jorge  Cuello, A Claudio 
Citation: Iulita MF, etal., Brain. 2014 Mar;137(Pt 3):860-72. doi: 10.1093/brain/awt372. Epub 2014 Feb 11.
RGD ID: 13204810
Pubmed: PMID:24519975   (View Abstract at PubMed)
PMCID: PMC3927704   (View Article at PubMed Central)
DOI: DOI:10.1093/brain/awt372   (Journal Full-text)

Basal forebrain cholinergic neurons play a key role in cognition. This neuronal system is highly dependent on NGF for its synaptic integrity and the phenotypic maintenance of its cell bodies. Basal forebrain cholinergic neurons progressively degenerate in Alzheimer's disease and Down's syndrome, and their atrophy contributes to the manifestation of dementia. Paradoxically, in Alzheimer's disease brains, the synthesis of NGF is not affected and there is abundance of the NGF precursor, proNGF. We have shown that this phenomenon is the result of a deficit in NGF's extracellular metabolism that compromises proNGF maturation and exacerbates its subsequent degradation. We hypothesized that a similar imbalance should be present in Down's syndrome. Using a combination of quantitative reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting and zymography, we investigated signs of NGF metabolic dysfunction in post-mortem brains from the temporal (n = 14), frontal (n = 34) and parietal (n = 20) cortex obtained from subjects with Down's syndrome and age-matched controls (age range 31-68 years). We further examined primary cultures of human foetal Down's syndrome cortex (17-21 gestational age weeks) and brains from Ts65Dn mice (12-22 months), a widely used animal model of Down's syndrome. We report a significant increase in proNGF levels in human and mouse Down's syndrome brains, with a concomitant reduction in the levels of plasminogen and tissue plasminogen activator messenger RNA as well as an increment in neuroserpin expression; enzymes that partake in proNGF maturation. Human Down's syndrome brains also exhibited elevated zymogenic activity of MMP9, the major NGF-degrading protease. Our results indicate a failure in NGF precursor maturation in Down's syndrome brains and a likely enhanced proteolytic degradation of NGF, changes which can compromise the trophic support of basal forebrain cholinergic neurons. The alterations in proNGF and MMP9 were also present in cultures of Down's syndrome foetal cortex; suggesting that this trophic compromise may be amenable to rescue, before frank dementia onset. Our study thus provides a novel paradigm for cholinergic neuroprotection in Alzheimer's disease and Down's syndrome.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Down syndrome  IDA 13204810 RGD 
Down syndrome  ISOMMP9 (Homo sapiens)13204810; 13204810 RGD 
Down syndrome  IEP 13204810 RGD 
Down syndrome  ISOTIMP1 (Homo sapiens)13204810; 13204810 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Mmp9  (matrix metallopeptidase 9)
Timp1  (TIMP metallopeptidase inhibitor 1)

Genes (Mus musculus)
Mmp9  (matrix metallopeptidase 9)
Timp1  (tissue inhibitor of metalloproteinase 1)

Genes (Homo sapiens)
MMP9  (matrix metallopeptidase 9)
TIMP1  (TIMP metallopeptidase inhibitor 1)


Additional Information