To identify the molecular mechanisms that lead to AD-typical neuropathological hallmarks transgenic mouse models proved to be a valuable tool. We have been characterizing the APP/PS1KI mouse model that closely mimics the development of AD related neuropathological features including a significant neuronal loss in the hippocampus, a structure involved in learning and memory processes21. Specific neurodegeneration in the hippocampal CA1 subfield and entorhinal cortex is an early event in the AD pathology that correlates directly with the severity of the disease22. As in post-mortem AD brain, it has been demonstrated that the APP/PS1KI mouse model harbours abundant N-modified A"42 including A"N3(pE). We therefore used this model to study a possible link between accumulation of A"N3(pE) and down-stream AD-typical pathological events. This transgenic mouse model carries M233T/L235P knocked-in mutations in presenilin-1 and overexpresses mutated human "-amyloid precursor protein. A"x-42 is the major form of A" species present in this model with progressive development of a complex pattern of N-truncated variants and dimers, similar to those observed in AD brain.
At the age of six months an age-dependent significant reduced ability to perform working memory and motoric tasks is seen in these mice. The APP/PS1KI mice were smaller and showed development of a thoralumbar kyphosis, together with reduced body weight, and axonal degeneration in brain and spinal cord23. At six months of age already a 33% CA1 neuron loss in the hippocampus, together with a drastic reduction of long-term potentiation was observed24.
CA1 neuron loss in these mice is likely to contribute to the working memory deficits and complete loss of synaptic plasticity (long-term potentiation) after stimulation of the Schaffer collaterals. Intraneuronal A" and peptides beginning with aspartate at position 1, and pyro-glutamate at position 3 were detected as early as two
|Contact: Thomas A. Bayer|
European College of Neuropsychopharmacology