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S1‐02‐01: Neuronal hypertrophy in asymptomatic Alzheimer's disease
Author(s) -
Troncoso Juan C.
Publication year - 2009
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2009.05.160
Subject(s) - gyrus , alzheimer's disease , hippocampus , posterior cingulate , pathology , autopsy , asymptomatic , neuroscience , medicine , psychology , cortex (anatomy) , disease
glutamatergic neurons differentiated from ES cells lacking both genes reveal a decreased expression of the vesicular glutamate transporter VGLUT2 expression, both at the mRNA and protein level. In addition, glutamate release assays indicate a reduced glutamate uptake and release, respectively. By contrast, a significant higher level of VGLUT2 transcription can be detected in differentiated neurons from ES cells overexpressing APP. These results point to an APP-dependent transcriptional complex regulating VGLUT2 gene expression, and blocking g-secretase cleavage of APP resulted in a similar decrease of VGLUT2 expression. Electrophysiological recordings of hippocampal organotypic slice cultures prepared from wild type mice and mice lacking APP and APLP2 corroborate these in vitro observations in vivo. EPSP amplitudes are reduced supporting a presynaptic defect in mice lacking APP and APLP2. Gene expression profiling and pathway analysis of the differentiated App-/-Aplp2-/neurons identified dysregulation of additional genes involved in synaptic transmission pathways. Conclusions: Our results indicate a significant functional role of APP and APLP2 in the development of synaptic function by the regulation of glutamatergic neurotransmission. Differentiation of ES cells into homogeneous populations thus represents a new opportunity to explore gene function and to dissect signalling pathways in neurons.