The present research evaluated the impact of chronic electric foot shock stress (before and after bilateral ICV-STZ injection) on body weight, spatial learning, memory, and hippocampal LRP1 and RAGE expression in a rat model of AD. According to the outputs, exposure to 10-day chronic electric foot shock stress decreased body weight, impaired spatial learning, and memory declined hippocampal LRP1 mRNA expression and enhanced hippocampal RAGE mRNA expression in the rat model of AD.
Weight loss and malnutrition have been identified as possible consequences of AD in studies. Additionally, weight loss is associated with rapid memory loss in patients with AD, emphasizing the importance of addressing weight loss and malnutrition in these patients (Gillette-Guyonnet et al., 2000; Kimura et al., 2019). Previously published research established that accumulating Aβ in the brain would impair the body's weight regulation mechanism; thus, resulting in increased weight loss years before AD diagnosis (Rabin et al., 2020). Further analyses revealed that ICV-STZ would cause syndromes mimicking the sporadic AD in the rats and thus produce an imbalance in the cerebral energy and declining body weight (K Paidi et al., 2015). The present research found animal weight loss following STZ injection into ventricles, similar to the observations reported by other researchers (K Paidi et al., 2015; Khalili & Hamzeh, 2010). On the other hand, stress has been shown to alter body weight and food intake in animal models (Geiker et al., 2018; Moreira, Almeida, Leite-Almeida, Sousa, & Costa, 2016). Consistent with our findings, multiple studies have demonstrated that chronic stress has no discernible effect on body weight compared to controls (Li, Zhang, & Huang, 2009; Liao et al., 2013). At the same time, several studies have found that chronic exposure to certain types of stressors causes either a decrease (Jeong, Lee, & Kang, 2013; Quan et al., 2011) or an increase (Geiker et al., 2018; Scott, Melhorn, & Sakai, 2012) in body weight. Diverse outputs may result from stress intensity, type, or duration variations. Intriguingly, our study found that rats lost a significant amount of weight following the accumulation of electric foot shock stress and STZ administration.
According to the studies in the field, learning and memory deficits have been proposed as the prime issues in AD, which prevent patients from enjoying everyday life (Jahn, 2013; White & Ruske, 2002). The results of our study and previous investigations confirmed a lower level of spatial learning and memory in the ICV-STZ animals on MWM (K Paidi et al., 2015; Negintaji et al., 2015; Sasaki-Hamada, Ikeda, & Oka, 2019). On the other hand, chronic stress would stimulate the enhanced levels of glucocorticoid stress hormones, which have detrimental impacts on the function and structure of the CNS, particularly the hippocampus (Conrad, 2010; Shors, 2004). We showed that chronic electric foot shock for ten days induced memory impairment in normal rats that matched earlier findings (Moosavi, Naghdi, Maghsoudi, & Asl, 2007; Wright & Conrad, 2008). Although there is insufficient information on the etiology of more common (sporadic) forms of AD, previous research indicated that the interaction of environmental risk factors and genetic backgrounds plays a significantly influential role in the onset and progression of sporadic AD. Epidemiological studies have identified stress as a risk factor for AD. The evidence suggested that AD would impair the normal functioning of the hypothalamic-pituitary-adrenal axis. The enhanced level of glucocorticoid can hit the hippocampus due to high levels of glucocorticoid receptors in the hippocampus of its neurons. Earlier research indicated that glucocorticoids and stress increased APP, BACE, and C99 levels, implying that stress induces APP processing along the amyloidogenic pathway, resulting in increased plaque formation and accelerating the neuropathology of AD, including increased Aβ deposition in the hippocampus (Cuadrado-Tejedor et al., 2012; Dong & Csernansky, 2009; Green, Billings, Roozendaal, McGaugh, & LaFerla, 2006). Also, studies conducted during the last decade found a relationship between levels of amyloid deposition and memory performance (Ford et al., 2015; Ramírez, Mendieta, Flores, & Limón, 2018). Hence, diverse spatial tasks have been utilized for assessing hippocampal functions, and MWM has been introduced as one of the classical tests of spatial learning and memory for rodents. A majority of the MWM investigations reported that chronic stress impaired spatial memory in the rat model of AD (Conrad, 2010; Vorhees & Williams, 2006). What was clear based on our findings is a considerable decline in spatial learning and memory when STZ coincided with chronic stress.
There is a correlation between neurological disorders, cerebrovascular dysfunction, and BBB function changes (Montagne, Zhao, & Zlokovic, 2017). Moving Aβ across BBB needs a professional transport system. Notably, LRP1 and RAGE receptors contribute significantly to the free un-bound Aβ between blood and brain and across BBB (Deane, 2012; Sagare et al., 2012). Moreover, neurodegenerative illnesses like AD showed more significant levels of RAGE and lower levels of LRP1 related to the Aβ toxicity-induced damages on the hippocampal cells (Erickson & Banks, 2013). Li Wang et al.'s (2017) study showed enhancement of RAGE and diminishment of LRP1 at BBB in the STZ-induced rat model of AD (L. Wang et al., 2017). In this sense, the present research confirmed the results obtained from earlier experiments. On the other hand, some investigations studied the impact of chronic and acute stress on the BBB functions (Kempuraj et al., 2019). A limited number of studies reported the correlation between chronic stress and BBB transport system dysfunction markers (Kempuraj et al., 2019). Our research revealed chronic electric foot-shock stress-induced lower LRP1 expression and greater RAGE expression in the rats' hippocampus. Based on the results of the previous studies, stress can exacerbate other disorders like depression (Plieger, Melchers, Montag, Meermann, & Reuter, 2015), metabolic syndrome (Tamashiro, Sakai, Shively, Karatsoreos, & Reagan, 2011), and diabetes (Pavlatou et al., 2008). Previous research has indicated that RAGE increased and LRP1 decreased at the BBB of STZ-induced diabetic rats. The results revealed that the upregulation of RAGE and downregulation of LRP1expression at the BBB contribute to Aβ deposition in diabetes mellitus (Hong et al., 2009; Liu et al., 2009). Additionally, Franklin et al. (2018) found that chronic unpredictable stress increased the mRNA levels of RAGE and high mobility group box one protein (HMGB1) in enriched hippocampal microglia. Furthermore, they demonstrated that RAGE deletion mutant mice are resistant to chronic unpredictable stress-induced behavioral deficits (Franklin et al., 2018). On the other hand, Wang et al. (2019) evidenced that chronic unpredictable mild stress increased hippocampal LRP1 expression in a depressive-like adult male rat model (H. Wang, Xiao, Wang, & Wang, 2020). The current research findings confirmed that electrical foot shock stress decreases LRP1 expression. The differences could be attributed to various factors, including the stress paradigm type and timing of stressors) used in the studies and the methodology used.