This review addresses this novel scenario, presenting data indicating that S100B levels and/or distribution in the nervous tissue of patients and/or experimental models of different neural disorders, for which the protein is used as a biomarker, are directly related to the progress of the disease: acute brain injury (ischemic/hemorrhagic stroke, traumatic injury), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis), congenital/perinatal disorders (Down syndrome, spinocerebellar ataxia-1), psychiatric disorders (schizophrenia, mood disorders), inflammatory bowel disease.
The discovery of neuroinflammatory changes, including dramatic proliferation of activated glia overexpressing a chromosome 2 gene product--the pluripotent immune cytokine interleukin-1 (IL-1)--and a chromosome 21 gene product--S100B--in the brains of fetuses, neonates, and children with DS opened the possibility that early events in Alzheimer pathogenesis were driven by cytokines.
HSA21 associated S100B and amyloid precursor protein (APP) levels are simultaneously increased within DS HNPs, their secretions are synergistically enhanced in a paracrine fashion, and overexpressions of these proteins disrupt mitochondrial membrane potentials and redox states.
We further demonstrate in DS NPCs that S100B is constitutively overexpressed, that overexpression leads to increased reactive oxygen species (ROS) formation and activation of stress response kinases, and that activation of this pathway results in compensatory AQP4 expression.
In humans, the gene for S100B is found on chromosome 21, within what is considered the obligate region for Down Syndrome (DS) and levels of S100B are increased in brain of both DS and Alzheimer's Disease (AD).
S100B overexpression correlates with Alzheimer pathology in post-adolescent Down syndrome patients and has been implicated in Abeta plaque pathogenesis.
S-100 beta, a gene triplicated in Down Syndrome (DS), is thought to play a role in development of the brain in general, and in the serotonergic neuronal system in particular.
In this regard, beta amyloid precursor protein (APP), CuZn superoxide dismutase (SOD1) and S100beta have been implicated in causing apoptosis, a mechanism thought to be responsible for neuronal loss in DS, in one way or another.
This study was devised to evaluate and compare the methods for detecting trisomy 21 by polymerase chain reaction (PCR)-associated analysis of small tandem repeats (STR) of D21S11 and semiquantitative analysis of S100B of chromosome 21.
A combined alteration such as up-regulation of S100beta together with down-regulation of Bcl-2 may be important in the pathogenesis of Alzheimer's disease and Down's syndrome.
S-100 b protein, the gene for which maps to the long arm of chromosome 21, (a) is overproduced in DS patients, (b) produces growth inhibition and differentiation of neural cells in vitro, (c) is abundant in good-prognosis neuroblastomas, and (d) has been shown to induce growth inhibition and differentiation and cell death in several human and murine neuroblastoma cell lines and could be responsible for this variation.
These results demonstrate an increase in S100 beta mRNA and protein levels during infancy indicative of postnatal astrocytic maturation and show that there is no gross deregulation in the expression of the S100 beta gene in DS as a consequence of trisomy 21.
It is postulated that S-100 b protein may inhibit the development of neuroblastomas in Down's syndrome either antenatally, or after birth and may be a therapeutic agent against neuroblastoma.
In Alzheimer's disease and Down's syndrome, severely afflicted brain regions exhibit up to 20-fold higher levels of S100 beta protein, and astrocytes surrounding neuritic plaques exhibit highly elevated levels of S100 beta immunostaining.
This raises the possibility that abnormalities in S100 protein gene dosage at a critical period during development may be responsible for some of the neurologic abnormalities associated with DS.