TRISOMY 16 AND NGF--EFFECTS ON CNS GENE EXPRESSION
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Several neuronal genes expressed in the CNS, including the amyloid beta protein precursor (APP) have been assigned to human chromosome 21 (HSA 21). Amyloid beta protein is an important component of cerebral vascular amyloid and the neuritic plaques seen in both Alzheimer's disease (AD) and trisomy 21 or Down syndrome (DS). Altered expression of APP or other genes on HSA 21 may contribute to the CNS abnormalities in both AD and DS. An animal model for DS, mouse trisomy 16, provides an opportunity to examine neuronal gene expression and to identify the abnormalities in APP expression induced by the trisomic state. Mouse chromosome 16 (MMU 16) contains at least 5 genes located on HSA 21 including APP. In addition, mice with trisomy 16(Ts 16 have both systemic and nervous system abnormalities similar to DS. To circumvent the problem of death in the late gestational period, chimeras (Ts 16<-->2N) will be used. Nerve growth factor (NGF) is a trophic factor for cholinergic neurons of the basal forebrain. As marked abnormalities of basal forebrain cholinergic neurons are found in both AD and DS, the influence of NGF on gene expression will be investigated. Analysis of mRNA for the genes encoding APP, the growth associated protein (GAP-43) and the prion protein (PrP) will be performed in basal forebrain and in several brain regions. These measurements will include analysis via Northern and slot/blot hybridization in normal mice and in chimeras. A number of different developmental stages will be assessed. The same procedures will be used to examine the response to exogenous NGF. In situ hybridization histochemistry (ISHH) will be used to localize and quantitate trisomic neurons in chimeras. Depending on results of initial studies, ISHH may be used to study mRNA levels in individual normal and trisomic cholinergic basal forebrain neurons. Studies of gene expression in the mouse model for DS may give fresh insights into the molecular pathogenesis of both AD and DS.
