Transgenic Mouse Models of Alzheimer's Disease

Abstract

Alzheimer’s disease is the most common cause of senile dementia in the United States and Europe. At present, there is no effective treatment. Given the disease’s prevalence and poor prognosis, the development of animal models has been a high research priority. Transgenic modeling has been pursued on the basis of the amyloid hypothesis and has taken advantage of mutations in the amyloid precursor protein and the presenilins that cause familial forms of Alzheimer’s disease. Modeling has been most aggressively pursued in mice, for which the techniques of genetic modification are well developed. Transgenic mouse models now exist that mimic a range of Alzheimer’s disease–related pathologies. Although none of the models fully replicates the human disease, the models have contributed significant insights into the pathophysiology of β-amyloid toxicity, particularly with respect to the effects of different β-amyloid species and the possible pathogenic role of β-amyloid oligomers. They have also been widely used in the preclinical testing of potential therapeutic modalities and have played a pivotal role in the development of immunotherapies for Alzheimer’s disease that are currently in clinical trials. These models will, without a doubt, continue to play central roles in preclinical testing and be used as tools for developing insights into the biological basis of Alzheimer’s disease.

Opportunities for Conformation-Selective Antibodies in Amyloid-Related Diseases

“…A number of reviews have been published describing animal models mimicking different neurodegenerative diseases in detail, including associated benefits and disadvantages [130][131][132][133]. Animal models provide opportunity to follow the disease development and progression and have been widely used to study factors that promote the Aβ plaque formation.…”

“…Also, findings generated in PS1 FAD mutant mice showing elevated level of Aβ42 and no plaques, have supported the toxic role of soluble Aβ. Tg2576 and 3xTg-AD mice models identified a 56kDa oligomeric toxic form of Aβ, which results in memory impairment in these mice, and when injected into rats disrupts cognitive functioning [130][131][132]. Thus, animal models can serve as complementary tools to validate conformational antibodies targeting specific oligomeric toxic forms of proteins and will continue to play a central role in improving existing knowledge of amyloid-based diseases and in preclinical testing of the current and novel therapeutic interventions.…”

“…This raises an important question as to which determinants: behaviour, synapse, dendritic responses, reduction in toxic species, inflammation, astroglial and microglial responses become the best measure and guide for drug development? It is important to remember that regardless of the impressive morphological resemblance to neurodegenerative disorders, extrapolating Tg mouse results to humans is not straight forward, as the triggering events of complex aging processes, and hence the exact pathway to the disease, are not necessarily the same in each individual [130][131][132].…”

Genetically Modified Animals in Pharmacology and Toxicology Research: Review

“…19 Ayrıca, Alzheimer hastalığının erken klinik dönemlerinde kullanılan Aβ aşısının güvenliği ve risk değerlen-dirmesi de yine transgenik farelerde yapılmıştır. 53 Gen tedavisi denemelerinde, kullanılacak maddelerin etkinliğinin belirlenmesinde genellikle indüklenmiş fare modellerinin kullanıldığı, ancak bulunabildiğinde büyük hayvanlarda oluşturulan spontan mutasyon modellerinin de etkinlik ve gü-venlik testleri için kullanılabileceği belirtilmiştir. 54 Bu konuyla ilgili olarak kalıtsal tirozinemi Tip 1 hastalık oluşturulmuş bir fare modelinde, fumarilasetoasetat hidrolazın (FAH) kaybının akut karaciğer yetmezliği, böbrek tübül hasarı ve karaciğer tümörlerine neden olduğu gösterilmiştir.…”

Inspiré par les lipides (Médaille Chevreul 2014)

“…Nous avons utilisé le modèle de souris Tg2576, qui a été largement utilisé pour de telles études. Il exprime la mutation de la protéine précurseur amyloïde humaine et commence à montrer une détérioration des fonctions cognitives et à accumuler des dépôts amyloïdes à l'âge de 8 mois environ (Elder et al, 2010).…”