Abstract
Alzheimer’s disease (AD) is the most common form of dementia in the elderly. It may be caused by oxidative stress, inflammation, and cerebrovascular dysfunctions in the brain. LongShengZhi Capsule (LSZ), a traditional Chinese medicine, has been approved by the China Food and Drug Administration for treatment of patients with cardiovascular/cerebrovascular disease. LSZ contains several neuroprotective ingredients, including Hirudo, Astmgali Radix, Carthami Flos (Honghua), Persicae Semen (Taoren), Acori Tatarinowii Rhizoma (Shichangpu), and Acanthopanax Senticosus (Ciwujia). In this study, we aimed to determine the effect of LSZ on the AD process. Double transgenic mice expressing the amyloid-β precursor protein and mutant human presenilin 1 (APP/PS1) to model AD were treated with LSZ for 7 months starting at 2 months of age. LSZ significantly improved the cognition of the mice without adverse effects, indicating its high degree of safety and efficacy after a long-term treatment. LSZ reduced AD biomarker Aβ plaque accumulation by inhibiting β-secretase and γ-secretase gene expression. LSZ also reduced p-Tau expression, cell death, and inflammation in the brain. Consistently, in vitro, LSZ ethanol extract enhanced neuronal viability by reducing L-glutamic acid-induced oxidative stress and inflammation in HT-22 cells. LSZ exerted antioxidative effects by enhancing superoxide dismutase and glutathione peroxidase expression, reduced Aβ accumulation by inhibiting β-secretase and γ-secretase mRNA expression, and decreased p-Tau level by inhibiting NF-κB-mediated inflammation. It also demonstrated neuroprotective effects by regulating the Fas cell surface death receptor/B-cell lymphoma 2/p53 pathway. Taken together, our study demonstrates the antioxidative stress, anti-inflammatory, and neuroprotective effects of LSZ in the AD-like pathological process and suggests it could be a potential medicine for AD treatment.
Highlights
Alzheimer’s disease (AD) is a disease accompanied by behavioral and cognitive impairment, which potently affects the normal social life of the elderly
We found L-glutamic acid (L-Glu) exposure increased reactive oxygen species (ROS) production to ∼two-fold (two-way ANOVA, F(2, 24) = 21.11, p = 0.0002) of that in the control group (Ctrl)
We found that treatment of HT-22 cells with L-Glu increased protein levels of interleukin 1β (IL-1β) (F(3, 16) = 170.3, p < 0.0001) and NF-κB (F(3, 16) = 9.999, p = 0.0010), which were blocked by LongShengZhi Capsule (LSZ)-EES treatment (F(3, 16) = 170.3, p < 0.0001 for IL-1β; F(3, 16) = 9.999, p = 0.0013 for NF-κB) (Figure 2C)
Summary
Alzheimer’s disease (AD) is a disease accompanied by behavioral and cognitive impairment, which potently affects the normal social life of the elderly. Amyloid-β (Aβ) plaques formed by aggregation of Aβ monomer and neurofibrillary tangles (NFTs) formed by hyperphosphorylation of microtubule-associated protein Tau (p-Tau) are considered the two critical biomarkers in AD brains (Congdon and Sigurdsson, 2018). Aβ is produced from amyloid-β precursor protein (APP) via the amyloidogenic pathway. APP is synthesized in the endoplasmic reticulum, transported to the Golgi apparatus, where it is mistakenly cleaved by β-secretase (BACE1) into β-N-terminal and β-Cterminal fragments. The N-terminal transmembrane region of the β-C-terminal fragment is further hydrolyzed by γ-secretase on the cell membrane to release an Aβ peptide (consisting of 39–43 amino acids), and the peptide further aggregates to form Aβ plaques (Hefter et al, 2020). The non-amyloidogenic pathway of APP cleavage, which is hydrolyzed by α- and γ-secretase, generates soluble α-APP, p3, and α-C terminal fragments (Dar and Glazner, 2020). In the brains of AD patients, the amyloidogenic pathway appears to be increased
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