Hesperidin Improves Memory Function by Enhancing Neurogenesis in a Mouse Model of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is an irreversible neurodegenerative disease characterized by memory and cognitive impairments. Neurogenesis, which is related to memory and cognitive function, is reduced in the brains of patients with AD. Therefore, enhancing neurogenesis is a potential therapeutic strategy for neurodegenerative diseases, including AD. Hesperidin (HSP), a bioflavonoid found primarily in citrus plants, has anti-inflammatory, antioxidant, and neuroprotective effects. The objective of this study was to determine the effects of HSP on neurogenesis in neural stem cells (NSCs) isolated from the brain of mouse embryos and five familial AD (5xFAD) mice. In NSCs, HSP significantly increased the proliferation of NSCs by activating adenosine monophosphate (AMP)-activated protein kinase (AMPK)/cAMP-response element-binding protein (CREB) signaling, but did not affect NSC differentiation into neurons and astrocytes. HSP administration restored neurogenesis in the hippocampus of 5xFAD mice via AMPK/brain-derived neurotrophic factor/tropomyosin receptor kinase B/CREB signaling, thereby decreasing amyloid-beta accumulation and ameliorating memory dysfunction. Collectively, these preclinical findings suggest that HSP is a promising candidate for the prevention and treatment of AD.

Survivin enhances hippocampal neurogenesis and cognitive function in Alzheimer's disease mouse model

“…Neural stem cells (NSCs) were obtained from the cortex and hippocampus of embryos on the embryonic day 14.5 fetuses as previously described 25 . The cerebellum, midbrain, olfactory bulb, and blood vessels of the embryo were removed.…”

“…Neural stem cells (NSCs) were obtained from the cortex and hippocampus of embryos on the embryonic day 14.5 fetuses as previously described. 25 The cerebellum, midbrain, olfactory bulb, and blood vessels of the embryo were removed. The cortex and hippocampus tissues were immersed in cold Ca 2+ /Mg 2+ ‐free Hanks' balanced salt solution (LB 203‐06; Welgene, Geongsan, Republic of Korea).…”

“…Cells were suspended as a single cell in an NSC medium: DMEM/F12 (LM‐002‐05; Welgene, Geongsan, Republic of Korea) supplemented with Penicillin/streptomycin (30010; Hyclone Laboratories, UT, USA), 1% N‐2 supplement (17502048; Gibco, MA, USA), 20 ng/mL EGF (PHG0311; Gibco, MA, USA), 20 ng/mL bFGF (PHG0368; Gibco, MA, USA), and 10% Insulin‐transferrin‐selenium‐sodium pyruvate (51,300,044; Gibco, MA, USA). 25 , 26 NSCs were seeded into 2 × 10 7 cells on a 100 mm cell culture dish. After day 3, NSCs were sub‐cultured with a fresh medium for proliferation or differentiation.…”

“…NSCs were cultured in an NSC medium: DMEM/F12 (LM‐002‐05; Welgene, Geongsan, Republic of Korea) supplemented with Penicillin/streptomycin (30010; Hyclone Laboratories, UT, USA), 1% N‐2 supplement (17502048; Gibco, MA, USA), 20 ng/mL EGF (PHG0311; Gibco, MA, USA), 20 ng/mL bFGF (PHG0368; Gibco, MA, USA), and 10% Insulin–transferrin–selenium–sodium pyruvate (51300044; Gibco, MA, USA) to proliferate into neurosphere as previously described. 25 After the secondary sub‐culture, the single cells of NSCs were seeded into 1 × 10 4 cells per well on a 96‐well plate. YM155 was treated 1 nM daily from the third day after subculture.…”

“…5‐Bromo‐2′‐deoxynridine (BrdU, B5002; Sigma‐Aldrich, MO, USA) injection was performed as described previously. 25 A month after stereotaxic injections, we treated BrdU intraperitoneally (50 mg/kg) for five consecutive days. BrdU was dissolved in 0.9% NaCl with 0.007 M NaOH.…”