Abstract
Alzheimer's disease (AD) is the most common type of dementia but lacks effective treatment at present. Gastrodin (GAS) is a phenolic glycoside extracted from the traditional Chinese herb—Gastrodia elata—and has been reported as a potential therapeutic agent for AD. However, its efficiency is reduced for AD patients due to its limited BBB permeability. Studies have demonstrated the feasibility of opening the blood-brain barrier (BBB) via focused ultrasound (FUS) to overcome the obstacles preventing medicines from blood flow into the brain tissue. We explored the therapeutic potential of FUS-mediated BBB opening combined with GAS in an AD-like mouse model induced by unilateral intracerebroventricular (ICV) injection of Aβ1-42. Mice were divided into 5 groups: control, untreated, GAS, FUS and FUS+GAS. Combined treatment (FUS+GAS) rather than single intervention (GAS or FUS) alleviated memory deficit and neuropathology of AD-like mice. The time that mice spent in the novel arm was prolonged in the Y-maze test after 15-day intervention, and the waste-cleaning effect was remarkably increased. Contents of Aβ, tau, and P-tau in the observed (also the targeted) hippocampus were reduced. BDNF, synaptophysin (SYN), and PSD-95 were upregulated in the combined group. Overall, our results demonstrate that FUS-mediated BBB opening combined with GAS injection exerts the potential to alleviate memory deficit and neuropathology in the AD-like experimental mouse model, which may be a novel strategy for AD treatment.
Highlights
Dementia, a syndrome characterized by dysfunction in memory, thinking, behavior, and the ability to perform daily activities, is affecting 50 million people globally
There was no EB staining in mouse brains at 24 h, 48 h, and 72 h after focused ultrasound (FUS) sonication (Figure 4), which indicates that FUS-mediated blood-brain barrier (BBB) opening in our experiment is reversible and the BBB closed within 24 h, avoiding the infectious risk of the central nervous system induced by long-term BBB opening
We processed the time that mice spent in the novel arm and the western blotting (WB) results via two-factor analysis of variance (ANOVA), trying to make it clear that whether the therapeutic effect of FUS+GAS. Combined treatment (FUS+GAS) is a result of additive effect
Summary
A syndrome characterized by dysfunction in memory, thinking, behavior, and the ability to perform daily activities, is affecting 50 million people globally. There are continuing nearly 10 million new cases each year. Alzheimer’s disease (AD) is the most common type of dementia, contributing to 60-70% of cases [1], generating physical, psychological, social, and economic impacts on patients, families, and society. AD is a neurodegenerative and one of the protein-conformation diseases [2, 3], pathologically characterized by extracellular beta-amyloid (Aβ) deposition, intracellular aggregation of neurofibrillary tangles (NFTs), and extensive loss of neurons [4, 5]. Aβ depositions contribute to proinflammation responses such as activation of microglia and astrocyte, synaptic dysfunction, and abnormal cell death [7, 8]
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