Trisomy 21 and the brain.
In fetuses with Down syndrome, neurons fail to show normal dendritic development, yielding a "tree in winter" appearance. This developmental failure is thought to result in mental retardation. In adults with Down syndrome, neuronal loss is dramatic and neurofibrillary and neuritic Abeta plaque pathologies are consistent with Alzheimer disease. These pathological changes are thought to underlie the neuropsychological and physiological changes in older individuals with Down syndrome. Two chromosome 21-based gene products, beta-amyloid precursor protein (betaAPP) and S100B, have been implicated in these neuronal and interstitial changes. Although not necessary for mental retardation and other features, betaAPP gene triplication is necessary, although perhaps not sufficient, for development of Alzheimer pathology. S100B is overexpressed throughout life in Down patients, and mice with extra copies of the S100B gene have dendritic abnormalities. S100B overexpression correlates with Alzheimer pathology in post-adolescent Down syndrome patients and has been implicated in Abeta plaque pathogenesis. Interleukin-1 (IL-1) is a non-chromosome-21-based cytokine that is also overexpressed throughout life in Down syndrome. IL-1 upregulates betaAPP and S100B expression and drives numerous neurodegenerative and self-amplifying cascades that support a neuroinflammatory component in the pathogenesis of sporadic and Down syndrome-related Alzheimer disease.
Mrak
Robert E
RE
Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Griffin
W Sue T
WS
D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001923:Brain Chemistry / Q000235:genetics*; D004314:Down Syndrome / Q000235:genetics* / Q000378:metabolism*; D004660:Encephalitis / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
D016564:Amyloid beta-Protein Precursor; D007375:Interleukin-1; D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579160:S100B protein, human; C579159:S100b protein, mouse