Abstract
The formation of neurofibrillary tangles has been implicated as an important pathological marker for Alzheimer's disease (AD). Studies have revealed that the inhibition of abnormal hyperphosphorylation and aggregation of tau in the AD brain might serve as an important drug target. Using in vitro and in vivo experimental models, such as the AD mouse model (5xFAD mice), we investigated the inhibition of hyperphosphorylation of tau using the human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs). Administration of hUCB-MSCs not only ameliorated the spatial learning and memory impairments but also mitigated the hyperphosphorylation of tau in 5xFAD mice. Furthermore, in vivo experiments in mice and in vitro ThT fluorescence assay validated galectin-3 (GAL-3) as an essential factor of hUCB-MSC. Moreover, GAL-3 was observed to be involved in the removal of aberrant forms of tau, by reducing hyperphosphorylation through decrements in the glycogen synthase kinase 3 beta (GSK-3β). Our results confirm that GAL-3, secreted by hUCB-MSC, regulates the abnormal accumulation of tau by protein-protein interactions. This study suggests that hUCB-MSCs mitigate hyperphosphorylation of tau through GAL-3 secretion. These findings highlight the potential role of hUCB-MSCs as a therapeutic agent for aberrant tau in AD.
Highlights
Alzheimer’s disease (AD) is a progressive, irreversible disorder characterized by amyloid plaques that form as a result of amyloid-beta (Aβ) accumulation and neurofibrillary tangles comprising of pathological tau aggregates [1]
We found that the transplanted hUCBMSCs were present in the brain parenchyma, including the cortex, hippocampal dentate gyrus (DG), caudate-putamen (CPu), hypothalamus, and subventricular zone (SVZ) (Figure 1(b))
To evaluate the changes in the cognitive function of AD mice due to hUCB-MSC administration, behavioral tests were conducted in both the hUCB-MSCtreated 5xFAD and phosphate-buffered saline (PBS)-injected control groups
Summary
Alzheimer’s disease (AD) is a progressive, irreversible disorder characterized by amyloid plaques that form as a result of amyloid-beta (Aβ) accumulation and neurofibrillary tangles comprising of pathological tau aggregates [1]. Hyperphosphorylation of tau protein in the AD brains induces aggregation of filament bundles [5], which are the hallmark of AD progression [6]. Neurofibrillary degeneration induced by aberrantly hyperphosphorylated tau is observed during the clinical evaluation of AD, which leads to cognitive impairments [7]. Pathological tau may result in microtubule dysfunction, leading to neuronal degeneration [8]. Lowering tau levels, stabilizing tau structure, or clearing hyperphosphorylated tau aggregates in the brain may be effective therapeutic strategies for AD. A therapeutic agent with an optimal efficacy has not yet been elucidated
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