Differential analysis of the physiological functions of GSK-3a/b isozymes in brain in vivo.

Fundamental questions as to the normal functions of APP and PS1 and how these are disturbed in AD, concern the amyloid peptides (Ab en 40) as well as the b-C-stubs (C99 fragment of APP after b- secretase cleavage). Whether they are 'triggers' of essential or of circumstantial mechanisms in neurodegeneration, also call to mind the problem of hyper-phosphorylation of tau, since tau- pathology is essential in AD. Besides this link, with implica- tions of disturbed axonal transport, is also the recent, unex- pected connection of mutant PS1 to neuronal calcium ion homeo- stasis to be considered. Neither the normal physiology, nor the pathology (neuro-toxicity), nor the trigger-mechanisms fundamen- tally known, while new therapeutic developments, mainly gamma- secretase inhibitors and vaccination with Ab peptides, awaken other fundamental questions.

Keywords:Dementia, Transgenic mice, Animal model

Disciplines:Biochemistry and metabolism, Medical biochemistry and metabolism