Date Published: September 20, 2017
Publisher: BioMed Central
Author(s): Lili Hu, Bingjie Wang, Yan Zhang.
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.
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.
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.
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.
The online version of this article (doi:10.1186/s13195-017-0304-4) contains supplementary material, which is available to authorized users.
Alzheimer’s disease (AD) is the most common form of dementia in people aged 65 years and older. AD is associated with impairments in memory, cognition, language, behavior, and personality . The pathology of AD in the brain includes extracellular senile plaques composed of amyloid beta (Aβ), intracellular tau aggregates known as neurofibrillary tangles (NFT), and neuronal and synaptic loss . Many studies have shown that individuals with the 267C allele of 5-HT6 have increased risk of AD [2, 3]. Several studies have reported that 5-HT6 has great impact in cognition, especially in AD models . Up to now, there is no effective treatment for AD. During the past 30 years, many studies have indicated that 5-HT6 may be a potential target for cognitive improvement in AD . Some 5-HT6 antagonists are currently being tested in clinical trials . However, although there is a strong link between 5-HT6 and AD development and treatment, the mechanism of how 5-HT6 is associated with AD is still not well understood. Besides, several 5-HT6 antagonist drugs, such as Pfizer’s SAM-760 and SAM-531, Abbott’s A-964324, Avineuro Pharmaceuticals’ AVN-322, Suven’s SUVN-502, Synosia Therapeutics’ SYN-120, idalorpidine, and others, showed no significant positive effects for AD patients . The clinical failures made the pathophysiology of 5-HT6 antagonist more uncertain and indicated the necessity to clarify the inner function of 5-HT6 in AD. In the present study, we aimed to determine the mechanism of 5-HT6 in AD pathology.
Previous studies showed that 5-HT6 is located at the primary cilia, where it plays an important role . Therefore, we suspected that 5-HT6 may influence cognition in AD patients by regulating the primary cilia function. The results of our study showed that overexpression of 5-HT6 increased the length of primary cilia. Meanwhile, 5-HT6 was upregulated in the hippocampus of APP/PS1 mice. 5-HT6, a G protein coupled receptor, not only regulated the cilia length and branch but also had an effect on the location of ARL13B and AnkG in primary cilia. 5-HT3A, which belongs to the Cys-loop superfamily of ligand-gated ion channels, also affected the cilia length. Both 5-HT6 and 5-HT3A are 5-HT receptors. This indicated that 5-HT receptors might cause the imbalance of some proteins and compromise ciliary signaling. The disorder of proteins in cilia could impair the ability of cilia to detect and respond to signaling in the local extracellular environment. As a result, ciliary function was influenced in APP/PS1 mice.
Our data showed that 5-HT6 regulated ciliary length through ARL13B, influenced the function of neuronal primary cilia, affected the AIS morphology and axonal length in APP/PS1 mice. Besides, SB271046, 5-HT6 antagonist, could recover the cognitive impairment of APP/PS1 mice. Based on our results and those of reported studies, 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.