In vivo and ex vivo analyses of amyloid toxicity in the Tc1 mouse model of Down syndrome.
RATIONALE
The prevalence of Alzheimer's disease is increased in people with Down syndrome. The pathology appears much earlier than in the general population, suggesting a predisposition to develop Alzheimer's disease. Down syndrome results from trisomy of human chromosome 21, leading to overexpression of possible Alzheimer's disease candidate genes, such as amyloid precursor protein gene. To better understand how the Down syndrome context results in increased vulnerability to Alzheimer's disease, we analysed amyloid-β [25-35] peptide toxicity in the Tc1 mouse model of Down syndrome, in which ~75% of protein coding genes are functionally trisomic but, importantly, not amyloid precursor protein.


RESULTS
Intracerebroventricular injection of oligomeric amyloid-β [25-35] peptide in three-month-old wildtype mice induced learning deficits, oxidative stress, synaptic marker alterations, activation of glycogen synthase kinase-3β, inhibition of protein kinase B (AKT), and apoptotic pathways as compared to scrambled peptide-treated wildtype mice. Scrambled peptide-treated Tc1 mice presented high levels of toxicity markers as compared to wildtype mice. Amyloid-β [25-35] peptide injection in Tc1 mice induced significant learning deficits and enhanced glycogen synthase kinase-3β activity in the cortex and expression of apoptotic markers in the hippocampus and cortex. Interestingly, several markers, including oxidative stress, synaptic markers, glycogen synthase kinase-3β activity in the hippocampus and AKT activity in the hippocampus and cortex, were unaffected by amyloid-β [25-35] peptide injection in Tc1 mice.


CONCLUSIONS
Tc1 mice present several toxicity markers similar to those observed in amyloid-β [25-35] peptide-treated wildtype mice, suggesting that developmental modifications in these mice modify their response to amyloid peptide. However, amyloid toxicity led to severe memory deficits in this Down syndrome mouse model.
['Naert|Gaëlle|G|', 'Ferré|Valentine|V|', 'Keller|Emeline|E|', 'Slender|Amy|A|', 'Gibbins|Dorota|D|', 'Fisher|Elizabeth Mc|EM|', 'Tybulewicz|Victor Lj|VL|', 'Maurice|Tangui|T|']
D000544:Alzheimer Disease D016229:Amyloid beta-Peptides D000818:Animals D015415:Biomarkers D002540:Cerebral Cortex D004195:Disease Models, Animal D004314:Down Syndrome D005260:Female D000071679:Glycogen Synthase Kinase 3 beta D006624:Hippocampus D007276:Injections, Intraventricular D008297:Male D008569:Memory Disorders D051379:Mice D008810:Mice, Inbred C57BL D018384:Oxidative Stress D010446:Peptide Fragments D012720:Severity of Illness Index
amyloid-β [25-35] peptide Tc1 mice memory Alzheimer’s disease tyrosine phosphorylation regulated kinase 1A gene