Abstract
Carboxy-dehydroevodiamine·HCl (cx-DHED) is a derivative of DHED, which improves memory impairment. Carboxyl modification increases solubility in water, indicating that its bioavailability is higher than that of DHED. Cx-DHED is expected to have better therapeutic effects on Alzheimer's disease (AD) than DHED. In this study, we investigated the therapeutic effects of cx-DHED and the underlying mechanism in 5xFAD mice, transgenic (Tg) mouse model of AD model mice. In several behavioral tests, such as Y-maze, passive avoidance, and Morris water maze test, memory deficits improved significantly in cx-DHED-treated transgenic (Tg) mice compared with vehicle-treated Tg mice. We also found that AD-related pathologies, including amyloid plaque deposition and tau phosphorylation, were reduced after the treatment of Tg mice with cx-DHED. We determined the levels of synaptic proteins, such as GluN1, GluN2A, GluN2B, PSD-95 and Rabphilin3A, and Rab3A in the brains of mice of each group and found that GluN2A and PSD-95 were significantly increased in the brains of cx-DHED-treated Tg mice when compared with the brains of Tg-vehicle mice. These results suggest that cx-DHED has therapeutic effects on 5xFAD, AD model mice through the improvement of synaptic stabilization.
Highlights
Alzheimer’s disease (AD), a common neurodegenerative disease, is characterized by amyloid beta (Aβ) plaque and intracellular neurofibrillary tangles (NFTs) (Cortese and Burger, 2016)
AD is the most common cause of dementia related to a progressive neurodegenerative disability, with a prevalence in 44 million people worldwide in 2015, and is estimated to double by 2050 (Van Cauwenberghe et al, 2016)
Soluble oligomeric Aβ has been detected in the brain tissues of patients with AD (Giuffrida et al, 2009) and demonstrated to be associated with memory and cognitive impairment (Shankar et al, 2008; Wilcox et al, 2011; Rijal Upadhaya et al, 2012)
Summary
Alzheimer’s disease (AD), a common neurodegenerative disease, is characterized by amyloid beta (Aβ) plaque and intracellular neurofibrillary tangles (NFTs) (Cortese and Burger, 2016). DHED prevented impairments of learning and memory in a scopolamine-induced memory impairment rat model (Park et al, 1996, 2000) and had beneficial effects on memory impairment and depressive-like behavior in a stressed rat model (Kim et al, 2014b). 5xFAD mice developed age-dependent behavioral deficits when studied using Y-maze, passive avoidance test, and Morris water maze test (Kim et al, 2014a; Webster et al, 2014). These characteristics make 5xFAD mice a robust model for investigating cx-DD’s pharmaceutical potential for the treatment of AD. We investigated the therapeutic effects of cxDD on memory loss from 4 months of age in 5xFAD mice and its underlying mechanisms
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