Chapter 12 - Alzheimer disease and neuroinflammation in Down syndrome: Effects of gene dosage and therapeutics

Abstract

Alzheimer disease (AD) in Down syndrome (DS) is a seamingly untreatable clinical event, which is characterized by aggregation of Aβ plaques, tau hyperphosphorylation, and neurofibrillary tangles in brain and exacerbates age-related dementia in individuals with DS. Unlike sporadic and familial AD, AD in DS (DSAD) occurs early, beginning at around 30 years of age with expression of AD features and overt dementia by 40 and 50 years, respectively. Overexpression of genes located on chromosome 21 (HSA21), APP and BACE2 in particular, and interaction among the trisomic and global disomic genes in DS accelerates overproduction of Aβ-protein amid processing, cleavage, and clearance of senile plaques. Gene-dosage effects on mitochondrial dysfunction and associated oxidative stress further aggravate the context of DSAD mechanism. Neuroinflammation accentuated by higher dosage of S100β, SOD1, ADAMTS1, ADAMTS5, CXADR, and many others genes results in activation of microglial cells and generation of cascade events, including abnormal release of cytokines and chemokines. Therapeutics for sporadic AD and DSAD on normalization of APP or active vaccination or passive immunization to introduce anti-Aβ antibodies in the DS population and AD patients have limited outcome in clinical trials and mouse models of DS. The present chapter has highlighted the critical aspects of DSAD with a keynote on requirement of further understanding of the genetic consequences of Aβ biology for prevention or treatment of the disease.