a-closed-loop-ta-vns-system-synchronized-with-bci-based-motor

A Closed-Loop ta-VNS System Synchronized with BCI-Based Motor Training for Post-Stroke Upper Limb Rehabilitation

Transcutaneous auricular vagus nerve stimulation (ta-VNS) involves applying electrical stimulation via electrodes to the auricular concha. This activates ...

The Third Affiliated Hospital of Sun Yat-sen University

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder leading to cognitive decline. Excessive cytosolic calcium (Ca) accumulation plays a critical role in the pathogenesis of AD since it activates the NOD-like receptor family, pyrin domain containing 3 (NLRP3), switches the endoplasmic reticulum (ER) unfolded protein response (UPR) toward proapoptotic signaling and promotes Aβ seeding. Herein, a liposomal nanodrug (felodipine@LND) is developed incorporating a calcium channel antagonist felodipine for Alzheimer's disease treatment through a low-intensity pulse ultrasound (LIPUS) irradiation-assisted blood brain barrier (BBB)-crossing drug delivery. The multifunctional felodipine@LND is effectively delivered to diseased brain through applying a LIPUS irradiation to the skull, which resulted in a series of positive effects against AD. Markedly, the nanodrug treatment switched the ER UPR toward antioxidant signaling, prevented the surface translocation of ER calreticulin (CALR) in microglia, and inhibited the NLRP3 activation and Aβ seeding. In addition, it promoted the degradation of damaged mitochondria via mitophagy, thereby inhibiting the neuronal apoptosis. Therefore, the anxiety-like behavior and cognitive impairment of 5xFAD mice with AD is significantly ameliorated, which manifested the potential of LIPUS - assisted BBB-crossing delivery of felodipine@LND to serve as a paradigm for AD therapy based on the well-recognized clinically available felodipine.

Blood Brain Barrier-Crossing Delivery of Felodipine Nanodrug Ameliorates Anxiety-Like Behavior and Cognitive Impairment in Alzheimer's Disease.

Alzheimer's disease (AD) affects thirty million individuals worldwide, but a viable treatment has yet to be identified. During disease progression, peripheral immune cells, including peripheral T cells, infiltrate the brain. Although CD4 regulatory T cells have been demonstrated to exhibit neuroprotective efficacy in AD, the precise roles of these cells in the brain remain elusive. Here, we report that β-amyloid (Aβ) 1-42 antigen-specific CD4 T cells spontaneously cross the blood-brain barrier (BBB) into the brain in an APP/PS1 mouse model. To promote parenchymal Treg conversion from infiltrated CD4 T cells and minimize the perturbations of the brain microenvironment, we engineered an Aβ1-42 antigen-specific CD4 T cell-based nanodelivery system to release the compound AS2863619, a CDK8/19 inhibitor (eTc-AS), which can bypass the BBB and selectively induce the conversion of CD4 T cells into Treg cells within the brain region. These cells demonstrated notable pathological amelioration in APP/PS1 mice, in part by interacting with microglia or recruited macrophage via PD-L1/PD-1 signaling. Our study reveals valuable engineered T cell therapies and suggests an immune checkpoint mechanism underlying the neuroprotective function of the Treg-microglia like cell interplay in AD.

Engineered peripheral CD4 T cells delivery across the BBB promote intracerebral Treg conversion unleashes microglial phagocytotic activity for Alzheimer's disease treatment.

Article	Year
Blood Brain Barrier-Crossing Delivery of Felodipine Nanodrug Ameliorates Anxiety-Like Behavior and Cognitive Impairment in Alzheimer's Disease. Advanced science (Weinheim, Baden-Wurttemberg, Germany)\| PubMed ID: 38981028	2024
Engineered peripheral CD4 T cells delivery across the BBB promote intracerebral Treg conversion unleashes microglial phagocytotic activity for Alzheimer's disease treatment. Biomaterials\| PubMed ID: 40763582	2026

Xiaofei He

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