Abstract
Background: Alzheimer’s disease (AD) is a fatal neurodegenerative disease characterized by progressive cognitive decline and memory loss. However, several therapeutic approaches have shown unsatisfactory outcomes in the clinical setting. Thus, developing alternative therapies for the prevention and treatment of AD is critical. Salidroside (SAL) is critical, an herb-derived phenylpropanoid glycoside compound, has been shown to attenuate lipopolysaccharide (LPS)-induced cognitive impairment. However, the mechanism underlying its neuroprotective effects remains unclear. Here, we show that SAL has a therapeutic effect in the senescence-accelerated mouse prone 8 (SAMP8) strain, a reliable and stable mouse model of AD. Methods: SAMP8 mice were treated with SAL, donepezil (DNP) or saline, and cognitive behavioral impairments were assessed using the Morris water maze (MWM), Y maze, and open field test (OFT). Fecal samples were collected and analyzed by 16S rRNA sequencing on an Illumina MiSeq system. Brain samples were analyzed to detect beta-amyloid (Aβ) 1–42 (Aβ1-42) deposition by immunohistochemistry (IHC) and western blotting. The activation of microglia and neuroinflammatory cytokines was detected by immunofluorescence (IF), western blotting and qPCR. Serum was analyzed by a Mouse High Sensitivity T Cell Magnetic Bead Panel on a Luminex-MAGPIX multiplex immunoassay system. Results: Our results suggest that SAL effectively alleviated hippocampus-dependent memory impairment in the SAMP8 mice. SAL significantly 1) reduced toxic Aβ1-42 deposition; 2) reduced microglial activation and attenuated the levels of the proinflammatory factors IL-1β, IL-6, and TNF-α in the brain; 3) improved the gut barrier integrity and modified the gut microbiota (reversed the ratio of Bacteroidetes to Firmicutes and eliminated Clostridiales and Streptococcaceae, which may be associated with cognitive deficits); and 4) decreased the levels of proinflammatory cytokines, particularly IL-1α, IL-6, IL-17A and IL-12, in the peripheral circulation, as determined by a multiplex immunoassay. Conclusion: In summary, SAL reversed AD-related changes in SAMP8 mice, potentially by regulating the microbiota-gut-brain axis and modulating inflammation in both the peripheral circulation and central nervous system. Our results strongly suggest that SAL has a preventive effect on cognition-related changes in SAMP8 mice and highlight its value as a potential agent for drug development.
Highlights
A prevalence-based study reported that the worldwide cost of dementia in 2015 was an enormous sum of US $818 bn, an increase of 35.4% compared to that in 2010 that was related to an increasing number of patients and rising costs per person (Wimo et al, 2017)
This study reports that SAL ameliorates cognitive decline in a reliable Alzheimer’s disease (AD) model, the senescence-accelerated mouse prone 8 (SAMP8) mouse strain, and has beneficial effects on the inflammation-related microbiota-gut-brain axis
The learning trials of the Morris Water Maze (MWM) revealed that SAMP8 required more time than senescence-accelerated mouse resistant 1 (SAMR1) mice to find the hidden platform and that escape latency was shortened by treatment with SAL or DNP (Figures 2B–D)
Summary
A prevalence-based study reported that the worldwide cost of dementia in 2015 was an enormous sum of US $818 bn, an increase of 35.4% compared to that in 2010 that was related to an increasing number of patients and rising costs per person (Wimo et al, 2017). Alzheimer’s disease (AD), as the primary cause of dementia, is a fatal neurodegenerative disease characterized by progressive cognitive decline and memory loss. The amyloid cascade hypothesis has been considered the main pathogenic concept in AD research for the past few decades This hypothesis suggests that the accumulation of amyloid-β (Aβ) peptide in brain tissue is the primary event in AD, followed by the formation of neurofibrillary tangles (NFTs) containing tau protein (Hardy and Selkoe, 2002). Alzheimer’s disease (AD) is a fatal neurodegenerative disease characterized by progressive cognitive decline and memory loss. Salidroside (SAL) is critical, an herb-derived phenylpropanoid glycoside compound, has been shown to attenuate lipopolysaccharide (LPS)-induced cognitive impairment. We show that SAL has a therapeutic effect in the senescence-accelerated mouse prone 8 (SAMP8) strain, a reliable and stable mouse model of AD
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