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Stéphanie Daumas"On Mice and Men: How Behavioural Studies on Transgenic Models Can Help Characterise Memory Loss in Alzheimer’s Disease"

Abstract :

Mouse models of Alzheimer’s Disease (AD) have been developed to exploit transgenic technology and the genetics of familial forms of AD.
Transgenic mice, overexpressing neuronal mutant human amyloid precursor protein (hAPP), have been shown to develop age-related synaptic changes, amyloid plaques and deficits in learning and memory. For instance, PDAPP mice (hAPPInd) are known to be impaired in spatial learning, but the psychological basis of this deficit is unclear. However, most of these studies have failed to recognize the contribution that marked overexpression of hAPP may have on these measures.
In a first study, we investigated age-dependent amyloid load, synaptic changes, neuronal activity and learning abilities in two different transgenic lines, the J9 and the I63. The J9 line expresses a low-level neuronal expression of hAPP carrying the Swedish and Indiana mutations (hAPPSw,Ind), whereas the I63 line overexpresses the wild-type hAPP (hAPPWT) at levels higher than that in the hAPPSw,Ind.
A key finding is that regional patterns of brain hypometabolism were detected before synaptic loss and in the apparent absence of cognitive alterations, although these came later in the mutant APP mice. The higher expression of human APP in the hAPPWT line also had a marked effect on synaptic loss. Together, these findings suggest that the expression of hAPP is not to be ignored in studies of mutant APP mice.
In this second study, our aim was to identify whether PDAPP mice display a progressive decline in cognitive dysfunction that in any way parallels that seen in patients. Using middle-aged animals PDAPP, we confirm a deficit in learning a spatial reference memory task and, after overtraining to an equivalent criterion of good navigational performance, that they also show faster forgetting. A deficit in serial spatial learning was not, at first, apparent in young mice prior to plaque deposition. However, a probe test revealed that a deficit in spatial memory was detectable, suggesting proactive interference due to the high demand levels of the task. PDAPP mice display faster forgetting, partly due to difficulties in accessing memory traces.
These findings raise the possibility that the age-related learning deficit is due, in part, to impaired hippocampal-dependent retrieval of memory traces. This interpretation of the learning deficit in hAPP mice has parallels to retrieval deficits observed in patients with AD, further supporting the validity of transgenic models of the disease. These data suggest that examining memory interference might be helpful in the early diagnosis of AD.

Selected publications

Daumas S, Betourne A, Halley H, Wolfer D, Lipp HP, Lassalle JM, Francés B (2006) Transient activation of the CA3 Kappa Opioid System in the dorsal hippocampus modulates complex memory processing in mice. Submitted.
Marchand S, Betourne A, Marty V, Daumas S, Halley H, Lassalle JM, Zajac JM, Francés B (2005) A Neuropeptide FF agonist blocks the acquisition of conditioned place preference to morphine in C57BL/6J mice. Peptides 27(5): 964-972

Daumas S, Halley H, Francés B, Lassalle JM (2005) Encoding, Consolidation and Retrieval of Contextual Memory: Differential Involvement of Dorsal CA3 and CA1 Hippocampal Subregions. Learning & Memory 12(4): 375-382

Jacques Micheau