Abstract
Amyloid-β1–42 (Aβ1–42) oligomers play an important role at the early stage of Alzheimer’s disease (AD) and have been a vital target in the development of therapeutic drugs for AD. Cajaninstilbene acid (CSA), a major bioactive stilbene isolated from pigeon pea (Cajanus cajan) leaves, exerted the neuroprotective property in our previous studies. The present study utilized a validated mouse model of early-stage AD induced by bilateral injection of Aβ1–42 oligomers into hippocampal CA1 regions (100 pmol/mouse) to investigate the cognitive enhancing effects of CSA and the underlying mechanism, by a combination of animal behavioral tests, immunohistochemistry, liquid chromatography-tandem mass spectrometry analysis, and Western blot methods. Intragastric administration of CSA (7.5, 15, and 30 mg/kg) attenuated the impairment of learning and memory induced by Aβ1–42 oligomers. CSA stimulated Aβ clearance and prevented microglial activation and astrocyte reactivity in the hippocampus of model mice. It also decreased the high levels of Glu but increased the low levels of GABA. In addition, CSA inhibited excessive expression of GluN2B-containing NMDARs and upregulated the downstream PKA/CREB/BDNF/TrkB signaling pathway. These results suggest that CSA could be a potential therapeutic agent at the early stage of AD.
Highlights
Alzheimer’s disease (AD) is a main form of dementia in the elderly and characterized by the accumulation of senile plaques which are composed of fibrillar amyloid-β peptide (Aβ) (Cohen and Calkins, 1959)
The results indicate that Cajaninstilbene acid (CSA) had no effects on the locomotor activity of mice
Our study provides a validated animal model to simulate the early stage of AD by bilateral injection of Aβ1–42 oligomers into the CA1 region of the hippocampus
Summary
Alzheimer’s disease (AD) is a main form of dementia in the elderly and characterized by the accumulation of senile plaques which are composed of fibrillar amyloid-β peptide (Aβ) (Cohen and Calkins, 1959). Recent experiments suggest that Aβ oligomers are more toxic than fibrils (Dahlgren et al, 2002; Balducci et al, 2010; DaRocha-Souto et al, 2011) and have already been detected in Abbreviations: CSA, cajaninstilbene acid; AD, Alzheimer’s disease; Aβ, amyloid β peptide; MWM, Morris water maze; Glu, glutamate; GABA, γ-aminobutyric acid; NMDARs, N-methyl-D-aspartate receptors; CREB, cAMP response element binding protein; PKA, cAMP-dependent protein kinase; BDNF, brain-derived neurotrophic factor; TrkB, tropomyosin receptor kinase B; sECC, stilbenes containing extract-fraction from Cajanus cajan (L.) leaves; HFIP, 1,1,1,3,3,3-hexafluoro-2-propanol; DMSO, dimethyl sulfoxide; PBS, phosphate buffered saline; AFM, atomic force microscopy; CMC-Na, carboxymethylcellulose sodium; OLR, object location recognition; PFA, paraformaldehyde; IOD, integrated optical density; MRM, multiple reactions monitoring; ANOVA, analysis of variance; LSD, least significant difference; LTP, long-term potentiation. Aβ1–42 oligomers play an important role at the early stage of AD
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