APP overexpression

The copper-binding APP and Ap have been proposed to play a role in physiological metal regulation. There is accumulating evidence of an unbalanced copper homeostasis with a causative or diagnostic link to AD. Whereas elevated copper levels are observed in APP knockout mice, APP overexpression results in reduced copper in transgenic mouse brain. Moreover, copper induces a decrease in Ap levels in APP-transfected cells in vitro. To investigate the... 

Cu metabolism altered in APPo/o and APP overexpressing cells and animals. 

A number of family mutations of the APP gene on chromosome 21 have been found, generally in early-onset AzD patients in different countries, all of which lead to increased jS-amyloid production. Also chromosome 21 is abnormally trisomic in Down Syndrome and most Down sufferers develop AzD if they reach 40 years. In transgenic mice, expressing familial AzD mutations of APP, the overexpression of APP is accompanied by increased amyloid deposition but whether this is due to the mutation or overexpression of APP is uncertain. Also not all the animals show memory loss and that tends to precede the amyloid disposition. 

Currently the only specific pharmacological therapeutic option available for AD patients is treatment with cholinesterase inhibitors, which provide moderate benefits in a subset of patients for a limited period [7]. More efficient future therapeutic strategies may be directed at the metabolic events resulting in Ap accumulation, for example by inhibition of P- or y-sec-retase [7], or at the prevention of neuronal loss by neurotrophin therapy [6]. The availability of transgenic mouse models of the disease, such as mice overexpressing APP mutants [8], and the utilization of primate models of cerebral amyloid [9] permits preclinical testing of novel diagnostic and therapeutic approaches. 

Wisselink, H. W., Mars, A. E., van der Meer, P., Eggink, G, and Hugenholtz, J. 2004. Metabolic engineering of mannitol production in Lactococcus lactis influence of overexpression of mannitol-1-phosphate dehydrogenase in different genetic backgrounds. App. Environ. Microbiol., 76,4286 1292. 

Lee EB, Zhang B, Liu K, Greenbaum EA, Dorns RW, Trojanowski JQ, Lee VM (2005) BACE overexpression alters the subcellular processing of APP and inhibits Abeta deposition in vivo. JCeUBiol 168(2) 291-302... 

Another mechanism preventing aggregation is the immunization against aggregated protein structures. A dramatic success had been archived using this method by Schenk et al. 1999 in the case of amyloid p [81]. He was able to prevent further amyloid deposition, in older mice that already had neuritic senile plaques due to a overexpression of a mutant form of the Alzheimer precursor protein (APP) that generates high level of amyloid p. 

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