3.2.1 Transgenic ALS rodent models used for evaluation of CNS barriers
In order to provide a review of the changes to CNS barriers in animal models of ALS, it is important to describe the commonly-used models of ALS. The human SOD1G93A transgenic mouse model, which harbors a mutation in human SOD1, was the first established animal model for ALS (Gurney et al., 1994; Rosen et al., 1993), which recapitulates many human ALS symptoms; mice first demonstrate a hindlimb tremor, followed by loss of the hindlimb splaying reflex, and eventually paralysis and death. Numerous SOD1 transgenic models of ALS were designed thereafter using patient sequence variants from genomic fragments, including the G37R mutation (Wong et al., 1995), the G86R mutation (Bartels et al., 2008), the G85R mutation (Bruijn et al., 1997), the L126Z mutation (Wang et al., 2005), and the T116X mutation (Han-Xiang et al., 2008). While each line differs in onset, presentation, and progression, SOD1 overexpressing transgenic mice generally share traits of significant motor neuron loss, axonal denervation, progressive paralysis, and reduced lifespan (Philips & Rothstein, 2015; Picher-Martel, Valdmanis, Gould, Julien & Dupré, 2016). In addition to the mouse model, a transgenic SOD1G93A rat model of ALS has been developed and validated, exhibiting a more rapid progression of disease (Howland et al., 2002). However, SOD1 models are based off a small fraction of an extremely heterogeneous disease, as only ~2% of human ALS (familial and sporadic) is due to SOD1 mutations (Picher-Martel, Valdmanis, Gould, Julien & Dupré, 2016). Therefore, findings obtained with this model need to be carefully considered as they may not be replicated in the majority of individuals with ALS.
While TAR DNA-binding protein 43 (TDP43) mutations only account for less than 5% of familial ALS cases, its identification as a causative gene to ALS in 2008 resulted in ~ 20 mouse models (Picher-Martel, Valdmanis, Gould, Julien & Dupré, 2016). The TDP43A315T mouse was the first reported TDP43 mutation-based ALS mouse model (Wegorzewska, Bell, Cairns, Miller & Baloh, 2009), which develops a gait abnormality, significant weight loss and a characteristic “swimming” gait.
While there exist other mouse models of ALS, such as FUS1-359 mice (Shelkovnikova et al., 2013) and C9orf72-based mouse models (Jiang et al., 2016; O’Rourke et al., 2015; Peters et al., 2015), they will not be described in detail as no studies assessing BBB or BSCB function have been reported in these animal models.