Dataset Information

Serotonin 5-HT6 receptors affect cognition in a mouse model of Alzheimer's disease by regulating cilia function.

ABSTRACT:

Background

Serotonin receptor 5-HT6 is involved in cognition and Alzheimer's disease (AD) development. However, the mechanism of 5-HT6 in AD pathology is not clear.

Methods

Since 5-HT6 is almost exclusively expressed in the primary cilia, using immunostaining we examined the number of cilia in the hippocampus of AD animal model APP/PS1 mice. By overexpressing and knocking down 5-HT6 in the primary cultured hippocampal neurons, we investigated the roles of 5-HT6 in alternating ciliary morphology. Furthermore, 5-HT6 antagonist was applied to confirm its roles in cognition using the Morris water maze test, Y maze, and fear conditioning.

Results

In the present study, we found that the primary cilia were elongated in the hippocampus of APP/PS1 mice compared with WT mice. 5-HT6 regulated cilia length, influenced cilia and axon initial segment (AIS) morphology, and affected localization of ARL13B and AnkG. We also found that, by changing cilia morphology, the AIS was elongated, branched, and more proximal to the cell body in both WT and APP/PS1 mouse neurons. Alterations of cilia also decreased the axonal length in WT and APP/PS1 neurons. Furthermore, in the water maze test, Y maze, and fear conditioning test, 5-HT6 antagonist SB271046 recovered the cognitive impairment of APP/PS1 mice.

Conclusion

We suggest that 5-HT6 plays a critical role in AD development through regulating the morphology and function of neuronal primary cilia, which is possibly related to the AIS and axon alterations in AD development.

SUBMITTER: Hu L

PROVIDER: S-EPMC5607612 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Publications

Serotonin 5-HT6 receptors affect cognition in a mouse model of Alzheimer's disease by regulating cilia function.

Hu Lili L Wang Bingjie B Zhang Yan Y

Alzheimer's research & therapy 20170920 1

<h4>Background</h4>Serotonin receptor 5-HT6 is involved in cognition and Alzheimer's disease (AD) development. However, the mechanism of 5-HT6 in AD pathology is not clear.<h4>Methods</h4>Since 5-HT6 is almost exclusively expressed in the primary cilia, using immunostaining we examined the number of cilia in the hippocampus of AD animal model APP/PS1 mice. By overexpressing and knocking down 5-HT6 in the primary cultured hippocampal neurons, we investigated the roles of 5-HT6 in alternating cili ...[more]

PMID: 28931427

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Project description:Alzheimer's disease (AD) is a neurodegenerative disorder with poorly understood etiology. AD has several similarities with other "Western lifestyle" inflammatory diseases, where the gut microbiome and immune pathways have been associated. Previously, we and others have noted the involvement of metabolite-sensing GPCRs and their ligands, short-chain fatty acids (SCFAs), in protection of numerous Western diseases in mouse models, such as Type I diabetes and hypertension. Depletion of GPR43, GPR41, or GPR109A accelerates disease, whereas high SCFA yielding diets protect in mouse models. Here, we extended the concept that metabolite-sensing receptors and SCFAs may be a more common protective mechanism against Western diseases by studying their role in AD pathogenesis in the 5xFAD mouse model. Both male and female mice were included. Depletion of GPR41 and GPR43 accelerated cognitive decline and impaired adult hippocampal neurogenesis in 5xFAD and WT mice. Lack of fiber/SCFAs accelerated a memory deficit, whereas diets supplemented with high acetate and butyrate (HAMSAB) delayed cognitive decline in 5xFAD mice. Fiber intake impacted on microglial morphology in WT mice and microglial clustering phenotype in 5xFAD mice. Lack of fiber impaired adult hippocampal neurogenesis in both W and AD mice. Finally, maternal dietary fiber intake significantly affects offspring's cognitive functions in 5xFAD mice and microglial transcriptome in both WT and 5xFAD mice, suggesting that SCFAs may exert their effect during pregnancy and lactation. Together, metabolite-sensing GPCRs and SCFAs are essential for protection against AD, and reveal a new strategy for disease prevention.Significance Statement Alzheimer's disease (AD) is one of the most common neurodegenerative diseases; currently, there is no cure for AD. In our study, short-chain fatty acids and metabolite receptors play an important role in cognitive function and pathology in AD mouse model as well as in WT mice. SCFAs also impact on microglia transcriptome, and immune cell recruitment. Out study indicates the potential of specialized diets (supplemented with high acetate and butyrate) releasing high amounts of SCFAs to protect against disease.

Dataset Information

Serotonin 5-HT6 receptors affect cognition in a mouse model of Alzheimer's disease by regulating cilia function.

Background

Methods

Results

Conclusion

Publications

Serotonin 5-HT6 receptors affect cognition in a mouse model of Alzheimer's disease by regulating cilia function.

Similar Datasets

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