Down syndrome (DS) is the most prevalent cause of intellectual disability (ID). Individuals with DS show a variety of cognitive deficits, most notably in hippocampal learning and memory, and display pathological hallmarks of Alzheimer's disease (AD), with neurodegeneration of cholinergic basal forebrain (CBF) neurons. Elucidation of the molecular and cellular underpinnings of neuropathology has been assessed via gene expression analysis in a relevant animal model, termed the Ts65Dn mouse. The Ts65Dn mouse is a segmental trisomy model of DS that mimics DS/AD pathology, notably age-related cognitive dysfunction and degeneration of basal forebrain cholinergic neurons (BFCNs). To determine expression level changes, molecular fingerprinting of cornu ammonis 1 (CA1) pyramidal neurons was performed in adult (4-9 month-old) Ts65Dn mice, at the initiation of BFCN degeneration. To quantitate transcriptomic changes during this early time period, laser capture microdissection (LCM), terminal continuation (TC) RNA amplification, custom-designed microarray analysis, and subsequent validation of individual transcripts by qPCR and protein analysis via immunoblotting was performed. The results indicate significant alterations within CA1 pyramidal neurons of Ts65Dn mice compared with normal disomic (2N) littermates, notably in the downregulation of neurotrophins and their cognate neurotrophin receptors among other classes of transcripts relevant to neurodegeneration. The results of this single-population gene expression analysis at the time of septohippocampal deficits in a trisomic mouse model shed light on a vulnerable circuit that may cause the AD-like pathology invariably seen in DS that could help to identify mechanisms of degeneration, and provide novel gene targets for therapeutic interventions. J. Comp. Neurol. 523:61-74, 2015. © 2014 Wiley Periodicals, Inc.
Keywords: Alzheimer's disease; BDNF; Down syndrome; RRID:AB_2314574, AB_397508, AB_2154265, AB_630940, AB_477580, AB_477262; RRID:IMSR_JAX:001924; TrkB; TrkC; hippocampus; laser capture microdissection; microarray; qPCR.
© 2014 Wiley Periodicals, Inc.