Abstract
Alzheimer’s disease (AD) is often characterized by the impairment of mitochondrial function caused by excessive mitochondrial fragmentation. Thrombospondin-1 (TSP-1), which is primarily secreted from astrocytes in the central nervous system (CNS), has been suggested to play a role in synaptogenesis, spine morphology, and synaptic density of neurons. In this study, we investigate the protective role of TSP-1 in the recovery of mitochondrial morphology and function in amyloid β (Aβ)-treated mouse hippocampal neuroblastoma cells (HT22). We observe that TSP-1 inhibits Aβ-induced mitochondrial fission by maintaining phosphorylated-Drp1 (p-Drp1) levels, which results in reduced Drp1 translocation to the mitochondria. By using gabapentin, a drug that antagonizes the interaction between TSP-1 and its neuronal receptor α2δ1, we observe that α2δ1 acts as one of the target receptors for TSP-1, and blocks the reduction of the p-Drp1 to Drp1 ratio, in the presence of Aβ. Taken together, TSP-1 appears to contribute to maintaining the balance in mitochondrial dynamics and mitochondrial functions, which is crucial for neuronal cell viability. These data suggest that TSP-1 may be a potential therapeutic target for AD.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by senile plaques, neurofibrillary tangles, mitochondrial dysfunction, and neuronal cell death[1]
Through Image J analysis of mitochondrial morphology using an index of aspect ratio and form factor (Fig. 1b, c), we observed that treatment with TSP-1 protein can block the amyloid β (Aβ)-induced mitochondrial fission
In this study, we found that TSP-1 has a protective role in Aβ-induced mitochondrial fission, mitochondrial dysfunction, and neuronal cell death (Supplementary Figure 3)
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by senile plaques, neurofibrillary tangles, mitochondrial dysfunction, and neuronal cell death[1]. Previous studies have reported that the amyloid β (Aβ) proteins are responsible for mitochondrial impairment during disease progression[2]. Mitochondrial accumulation of Aβ is directly associated with neuronal toxicity, which can contribute to neuronal cell death in AD3. Mitochondrial function is crucial for cell survival. The mitochondria are responsible for ATP production through oxidative phosphorylation (OXPHOS), conduction of signals, and regulation of programmed cell death[4].
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