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P1–109: Age–dependent changes in hippocampal glutamate levels parallel learning impairment in APP/PS1 transgenic mice
Author(s) -
Minkeviciene Rimante,
Ihalainen Jouni,
Malm Tarja,
Leguit N.,
Glen J.,
Banerjee Pradeep K.,
Tanila Heikki
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.2006.05.485
Subject(s) - glutamate receptor , astrogliosis , nmda receptor , microdialysis , hippocampal formation , hippocampus , neurotoxicity , medicine , endocrinology , genetically modified mouse , extracellular , microglia , amyloid precursor protein , alzheimer's disease , chemistry , receptor , toxicity , central nervous system , transgene , biochemistry , inflammation , disease , gene
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.