Brain G protein-dependent signaling pathways in Down syndrome and Alzheimer’s disease

Abstract

Premature aging and neuropathological features of Alzheimer's disease (AD) are commonly observed in Down syndrome (DS). Based on previous findings in a DS mouse model, the function of signaling pathways associated with adenylyl cyclase (AC) and phospholipase C (PLC) was assessed in cerebral cortex and cerebellum of age-matched adults with DS, AD, and controls. Basal production of cAMP was reduced in DS but not in AD cortex, and in both, DS and AD cerebellum. Responses to GTPgammaS, noradrenaline, SKF 38393 and forskolin were more depressed in DS than in AD cortex and cerebellum. Although no differences in PLC activity among control, DS and AD cortex were observed under basal and GTPgammaS- or Ca-stimulated conditions, the response of DS cortex to serotonergic and cholinergic stimulation was depressed, and that of AD was only impaired at cholinergic stimulation. No differences were documented in cerebellum. Our results demonstrate that PLC and AC were severely disturbed in the aged DS and AD brains, but the alterations in DS were more severe, and differed to some extent from those observed in AD.

G-Protein-Associated Signal Transduction Processes Are Restored after Postweaning Environmental Enrichment in Ts65Dn, a Down Syndrome Mouse Model

“…However, when the system was challenged by receptor stimulation of β-adrenoceptor, or using GTPγS, a nonhydrolyzable analog of GTP, or forskolin to directly activate the catalytic subunit of the enzyme, an impaired response was clearly detected in the trisomic mice. Our present results confirm the deficits we reported in the frontal and hippocampal cortices of young adult male Ts65Dn mice [29,30], and in DS individuals [21], where we observed a severe deficiency in AC activity, with a very poor response to various stimulatory signals, including forskolin [21]. In the present work, this reduction was also detected in the hippocampus of Ts65Dn females that could be related to their learning deficits.…”

“…Numerous studies have revealed disrupted post-receptor signal transduction, in particular those mediated by G-protein-regulated adenylyl cyclase (AC) [19,20,21,22] and phospholipase C (PLC) [21,22,23,24] in DS brains. Consistent changes found in myoinositol and phospholipid composition of fetal and adult DS brain membranes [25,26,27] may predict deregulation of PLC-linked transduction processes, and our previous studies determined a reduced ability of several brain areas to respond to the indirect (receptor-mediated) and direct stimulation of the PLC [28] and AC [29,30] signaling systems in Ts65Dn mice.…”

Functional genomic analysis of amniotic fluid cell-free mRNA suggests that oxidative stress is significant in Down syndrome fetuses

“…Another study using adult mouse models has suggested a role for two other G protein dependent pathways in DS and Alzheimer disease (34). Our work, however, suggests a wider and more fundamental role for G protein signaling, involving a large number of proteins and appearing as early as the second trimester.…”

Comprehensive behavioral assays to enhance phenotype to genotype linkages and therapeutic screening in mouse models of Down syndrome

“…This model replicates many physical and functional abnormalities observed in people with trisomy for chromosome 21. The abnormalities include shorter life expectancies and morphological, neurological, behavioral, structural, and neuronal circuit abnormalities that parallel those in people with DS [8][9][10][11][12][13][14][15]. Furthermore, consistent with the changes demonstrated in imaging and behavioral studies in people with DS [5][6][7], the Ts65Dn model displays deficits in hippocampal structure and function.…”

“…In spite of significant recent progress in understanding the neurobiology of DS [8][9][10][11][12][13][14][15][16][17], there is as yet little insight into the genes and mechanisms responsible for developmental and age-related changes in cognition and behavior. The 'gene dosage' hypothesis for exploring pathogenesis states that an extra copy of one or more genes, or regulatory elements, on HSA21 is responsible for the changes in brain structure and function -in other words, for all the phenotypes that are characteristic of DS.…”