The Involvement Of Serotoninergic Receptor (5-HTR) In BPSD Of Alzheimer's Disease

Background Alzheimer's disease(AD)is the most common neurodegenerative disease.More than 90% of patients with AD develop behavioral and psychological symptoms of dementia(BPSD).There is greater heterogeneity among affected individuals.Clinical manifestations include psychomotor excitement,mood disorders(such as anxiety,depression,and apathy)and mental symptoms(such as delusions and hallucinations),etc.These are the primary reasons for AD patients to be hospitalized.But the underlying mechanism of BPSD symptoms is unclear,and the targeted drug is lacking either.Previous evidence has shown that alteration in serotonin neurotransmitter(5-hydroxytryptamine,5-HT)pathway is related to the onset and development of BPSD,and selective serotonin reuptake inhibitors(SSRIs)have been used clinically as antidepressants.There are 14 families and 27 5-HT receptor subtypes(5-HTRs)discovered so far,however their biological function is unclear yet.Thus,this work aim to study the relationship between 5-HTR1 A,5-HTR2 A,5-HTR2 C,5-HTR6 and 5-HTR7 the 5 key subtypes and AD+BPSD symptom.Objectives This study determined that APP / PS1 mice are available AD + BPSD animal models,studied the temporal and spatial relationship between 5-HTRs and the onset and development of BPSD,and proof the biological links and related molecular pathological mechanisms between the 5-HTRs and AD + BPSD.Method Both in vivo and in vitro studies were conducted.First,with 3-and 12-month-old animal model of APP / PS1 double transgenic positive mice,we investigated: 1)behavioral tests to detect the presence of AD + BPSD-like behavior including: open field,elevated plus maze,Morris water maze,and fear conditioning system;2)A? plaques in the hippocampal region of the APP / PS1 mice with Thioflavin T fluorescence staining;3)the protein expression levels of the 5-HTR subtypes including: 5-HTR1 A,5-HTR2 A,5-HTR2 C,5-HTR6 and 5-HTR7 in the hippocampus,temporal,prefrontal cortex and amygdala of APP / PS1 mouse using Western blot.Then,with AD cell model,we detected the pathological changes in 5-HTRs: 1)constructed AD cell model using SH-SY5 Y neuroblastoma cell line infected by A?25-35;2)detected the protein levels of 5-HTRs in cell model.Results We found:1)in the 3-month-old APP / PS1 mouse model,spatial learning and memory deficits and an increase in 5-HTR6 protein expression in the temporal lobe were observed,but no other visible abnormalities in BPSD-like behavior.There was no significant abnormalities in the expression of each of the 5-HTRs subtypes in other brain regions.2)In the 12-months-old APP / PS1 mouse,AD mice showed spatial learning and memory impairment and anxiety,suggesting BPSD-like behavior abnormalities,and increased A? plaques in hippocampus and abnormal expressions of subtypes of 5-HTRs also found.Among them,the expression of 5-HTR6 was significantly reduced in the hippocampus,and the expression of 5-HTR2 A and 5-HTR6 in amygdala was also significantly reduced.3)To find the underlying mechanisms that caused the reduced expression of 5-HTRs,the expression of 5-HT transporter SERT was tested.The expression of SERT was significantly reduced in the hippocampal.4)In vitro study used AD cell model,we found that 5-HTR6 expression was significantly reduced under A? induction.Conclusion Different 5-HTR subtypes has abnormal expression in different brain region and different time point in AD mice.Accompanied with the occurrence of BPSD,5-HTRs may have a potential correspondence with the occurrence and development of AD + BPSD symptoms.