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P1–108: Gene expression changes after MAPT expression inhibition
Author(s) -
Golan Maciej P.,
Lewis Jada,
McKinney Michael,
Kent Caroline,
Gass Jennifer,
Heckman Mike,
Crook Julia,
Hutton Michael L.
Publication year - 2006
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.2006.05.484
Subject(s) - tauopathy , neurodegeneration , transgene , tau protein , biology , neuroscience , genetically modified mouse , gene expression , downregulation and upregulation , microarray analysis techniques , microbiology and biotechnology , gene , alzheimer's disease , genetics , medicine , disease
Ts65Dn mice, but not Ts1Cje, exhibited significantly reduced T2 relaxation times selectively in the medial septal area, from where BFCN originate, and in brain regions normally innervated by BFCN, including hippocampus and cingulate cortex. BFCN projections to these areas, identified by choline acetyltransferase (CHAT) immunocytochemistry or acetylcholinesterase histochemistry, were selectively and markedly reduced in Ts65Dn mice and numbers of detectable BFCN in the medial septal area, identified by CHAT or p75NGFR immunolabeling, were significantly below normal. In BFCN projection areas of the cortex, dendrites in Ts65Dn brain displayed morphological changes and markedly increased levels of MAP-2, a cytoskeletal protein regulated by cholinergic innervation. Using electron microscopy and antibody markers for apoptosis pathway activation, we detected a higher than normal frequency of neurons undergoing apoptosis in affected brain regions. Conclusions: MRI revealed more widespread neuropathology in Ts65Dn mice than previously appreciated, involving postsynaptic as well as presynaptic elements of the BFCN circuit. The cholinergic deficits, MRI T2 changes, and AD-related endosomal phenotype in Ts65Dn mice, but not Ts1Cje, support growing evidence linking APP triplication to endosome dysfunction (A.Boyer-Boiteau; et al., this meeting), retrograde signaling deficits, and increased vulnerability of neurons to degeneration.