Recently, the Shanghai-based company Green Valley announced approval of their drug candidate Oligomannate for clinical use in mild to moderate Alzheimer’s disease (AD) in China. This news made a big splash because nearly two decades have passed since the last approval of an Alzheimer’s drug. The successful approval of this drug was partially based on preclinical studies performed in 5xFAD mice (Wang et al., 2019). Available at QPS Neuropharmacology, 5xFAD mice are a well-known and often used rodent model in the preclinical AD research community (Oakley et al., 2006). These mice display the most common AD pathologies quite early, starting at 5 to 6 months of age. An alternative rodent model that shows very similar AD-related changes at a slightly later onset are APPSL mice (Havas et al., 2011).
The phenotypes of both mouse models are characterized by learning and memory deficits, the most prominent symptom in AD patients. Animals show APP plaques in different brain regions and also increased Aβ1-40 and Aβ1-42 levels in the brain and cerebrospinal fluid. Additionally, animals present distinct neuroinflammation that is often associated with plaques. Increased oxidative stress, a disturbed blood-brain-barrier homeostasis, and cerebral amyloid angiopathy (CAA) can be measured in both models as well.
While in other animal models rarely detectable, pathologies including increased levels of pyroglutamated Aβ (Aβ-pE(3)), known to be strongly elevated in AD patients, and increased levels of phosphorylated tau protein are seen in 5xFAD and APPSL mice. Although only endogenous tau is present in these animals, increased phosporylation levels can be detected and significantly increase over age in 5XFAD and also APPSL mice (see image below).
So both 5xFAD and APPSL mice resemble the human AD pathology in many ways, including brain pathology, behavior, and biomarkers. Recently, neurofilament light chain has been highly discussed as a valuable biomarker for different neurodegenerative disorders like AD. Preliminary results by QPS Neuropharmacology, communicated in the poster Characterization of relevant mouse models for new biomarkers, could validate a progressive increase of neurofilament light chain in 5xFAD mice. Analysis of APPSL mice for this biomarker is still in progress.
Overall, the phenotypes of 5xFAD and also APPSL mice and the study by Wang and colleagues of Green Valley further foster the merit of AD-relevant mouse models for preclinical AD research. They give hope that the AD research community will soon be successful in finding an effective treatment against AD symptoms – and maybe even a cure for the disease.
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