An attempt to establish criteria for such animal models was made the same year. The ?rst tools described as animal models of AD were based on etiological considerations of the disease, whether chronic aluminum intoxication or excitotoxic lesions of choli nergic neurotransmission was thought to be at the origin of the neurodegeneration. The early 1990s saw the appearance of the ?rst transgenic www.selleckchem.com/products/Calcitriol-(Rocaltrol).html mouse models of AD, nearly a decade after the discovery of the ?rst mutation in the gene encoding the amyloid precursor protein and its central role in the familial form of AD. These models, which carried a mutated form of the human APP gene, were found to be unsatisfactory, and double transgenic mice carrying two human mutated transgenes, APP PS1 or APP tau, were developed.

Inhibitors,Modulators,Libraries This was Inhibitors,Modulators,Libraries soon followed by the APP PS1 Inhibitors,Modulators,Libraries tau triple trans genic mouse model. The strategy behind the development of these models was to reproduce patho logical features observed in AD, including the sporadic form, rather than tackle the etiology of AD. This con sideration justi?ed the use of the transgene tauP301L, a mutation of the gene encoding the tau protein that is not encountered in AD but pertains to the frontotemporal dementia with Parkinsonism linked to chromosome 17. Although the rat has been the animal of choice for drug development and fundamental research for decades, it progressively faded away in favor of mice, a species in which genetic manipulation is much easier and for which there is a greater variety of research reagents available.

These transgenic models contributed tremendously to our understanding of the molecular mechanisms in volved in the onset and progression Inhibitors,Modulators,Libraries of the disease. Transgenic mouse models of AD helped decipher the secretory pathway of APP and the production of AB42 through APP cleavage by B and secretases, thus improving our understanding of AD pathogenesis. In addition, Inhibitors,Modulators,Libraries these animal models provided evidence about the physiological role played by APP, APP fragments and secretase in processes like neurogenesis and the mechanism underlying memory consolidation. It is undeniable that transgenic mouse models of AD led the way of the fundamental research so far conducted on understanding the disease. Moreover, it is critical to mention the primordial role played by the transgenic mouse models in the development of tracers for magnetic resonance imaging and positron emission tomo graphy imaging and in the characterization of new biomarkers.

However, transgenic mouse models have some limitations. thoroughly First, unlike the human neuropathology, which displays massive neurodegenera tion, only very few models show neuronal death and on a scale that does not compare to what is seen on postmortem human brains. Second, the way the genetic manipulation translates into the histological and clinical recapitulation of the disease highly depends on the promoter used to insert the transgene and on the genetic background of the recipient animal.