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O2–04–07: A Serial Analysis of Gene Expression (SAGE) profile of the Alzheimer's disease TG2576 mouse model
Author(s) -
George Amee J.,
Gordon Lavinia,
Beissbarth Tim,
Koukoulas Irene,
Holsinger R.M. Damian,
Perreau Victoria,
Cappai Roberto,
Tan Seong Seng,
Masters Colin L.,
Scott Hamish S.,
Li Qiao-Xin
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.2006.05.135
Subject(s) - serial analysis of gene expression , gene , biology , gene silencing , gene expression , genetics , genetically modified mouse , microarray analysis techniques , alzheimer's disease , computational biology , gene expression profiling , transgene , disease , medicine , pathology
amyloid precursor protein APP751 (KM670/671NL and V717I) and knocked-in human mutant presenilin-1 (M233T/L235P), named APP751/ PS1KI. The objective was to study intraneuronal pathology and consequences of neuron loss. Methods: mRNA profiling, neuropathology of brain and spinal cord, 2D gel electrophoresis, stereology. Conclusions: Substantial neuron loss was found in the hippocampal pyramidal CA1/2 layer at six months ( 20%), and at 10 months of age ( 50%). The loss of neurons did not correlate with plaque load. Most remarkable, using 2D-gel electrophoresis, the mice exhibited a heterogeneous variety of N-truncated and modified A 42 peptides. Before plaque formation, we could detect intraneuronal oligomeric A accumulation and peptides beginning with aspartate at position 1 (Land D), and glutamate at position 3 (pyro-Glu), the latter has been shown to be the most prominent species in sporadic AD brains. Interestingly, using Chip-based mRNA profiling and qRT-PCR verification, we identified several mRNAs involved in iron/copper homeostasis, which were up-regulated in an age-dependent manner. In the spinal cord, signs for Wallerian degeneration and axonal transport problems in an age dependent manner were observed. Overall, the mouse model shows major AD-typical neuropathological hallmarks with abundant neuron loss that is clearly independent from extracellular amyloid deposition and identifies intraneuronal A X-42 as a major neurotoxic risk factor. Moreover, pathological signs, like demyelination, gliosis and deteriorated axon tracts, markers for axonal degeneration are found independent from extracellular A depositions. We suggest a modified amyloid hypothesis with intracellular aggregation as the major toxic factor, which induces axonal mistrafficking, and neurodegeneration. N-truncated and modified A peptides are of particular importance, because they are more stable and are therefore at higher risk for intraneuronal aggregation.