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Functional and morphological alterations in compound transgenic mice overexpreszing Cu/Zn superoxide dismutaze and amyloid precursor protein
Author(s) -
HarrisCerruti Catherine,
Kamsler Ariel,
Kaplan Batia,
Lamb Bruce,
Segal Menahem,
Groner Yoram
Publication year - 2004
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2004.03188.x
Subject(s) - sod1 , amyloid precursor protein , superoxide dismutase , lipofuscin , chromosome 21 , genetically modified mouse , hippocampal formation , long term potentiation , synaptic plasticity , microbiology and biotechnology , biology , chemistry , transgene , endocrinology , medicine , alzheimer's disease , biochemistry , oxidative stress , gene , chromosome , receptor , disease
Down's syndrome (DS), the phenotypic manifestation of trisomy 21, involves overexpression of chromosome 21‐encoded genes. The gene for amyloid precursor protein (APP), known to be involved in AD pathology, resides on chromosome 21 along with the gene for Cu/Zn superoxide dismutase (SOD1), a key enzyme in the metabolism of oxygen free radicals. We investigated the consequences of a combined increase in APP and SOD1, in a double‐transgenic (tg)‐APP–SOD1 mouse. These mice expressed severe impairment in learning, working and long‐term memory. Expression of long‐term potentiation in hippocampal slices was impaired in both tg‐SOD and tg‐APP–SOD mice, but not in tg‐APP mice, indicating that increased APP by itself did not affect in vitro synaptic plasticity. In tg‐APP–SOD mice, membrane‐bound high molecular weight APP species accumulated while APP cleavage products did not increase and levels of secreted APP were unchanged. Severe morphological damage, including lipofuscin accumulation and mitochondria abnormalities, were found in aged tg‐APP–SOD but not in the other mice. Thus, a combined elevation of the two chromosome 21 genes in tg‐APP–SOD mice induced age‐dependent alterations in morphological and behavioural functions.