Serotonin-2B receptor (5-HT_2BR) expression and binding in the brain of APP_swe/PS1_dE9 transgenic mice and in Alzheimer's disease brain tissue

TY - JOUR

T1 - Serotonin-2B receptor (5-HT2BR) expression and binding in the brain of APPswe/PS1dE9 transgenic mice and in Alzheimer's disease brain tissue

AU - Anzalone, Marco

AU - Karam, Sarmad A

AU - Briting, Sanne R R

AU - Petersen, Sussanne

AU - Thomsen, Majken B

AU - Babcock, Alicia A

AU - Landau, Anne M

AU - Finsen, Bente

AU - Metaxas, Athanasios

PY - 2025/1/1

Y1 - 2025/1/1

N2 - Despite well-documented dysregulation in central serotonergic signaling in Alzheimer's disease (AD), knowledge about the potential involvement of the serotonin-2B receptor (5-HT2BR) subtype remains sparse. Here, we assessed the levels of 5-HT2BRs in brain tissue from APPswe/PS1dE9 transgenic (TG) mice, AD patients, and adult microglial cells. 5-HT2BR mRNA was measured by RT-qPCR in ageing TG and wild-type (WT) mice, in samples from the middle frontal gyrus of female, AD and control subjects, and in microglia from the cerebral cortex of WT mice. The density of 5-HT2BRs was measured by autoradiography using [3H]RS 127445. Both mouse and human brains had low levels of 5-HT2BR mRNA. In whole-brain mouse samples, mRNA expression was significantly lower in TG mice compared to WT at > 18 months of age. In the Aβ-plaque-burdened neocortex and hippocampus of old TG mice, however, levels of 5-HT2BR mRNA were two-fold higher over control, with similar elevations observed in the Aβ-plaque-burdened frontal cortex of human AD patients. 5-HT2BR mRNA expression varied widely in adult microglia and was higher compared to other cortical cell subtypes. In mice, specific [3H]RS-127445 binding in the cortex was first detected after 3 months of age. The density of 5-HT2BRs was low and overall reduced in TG, compared to WT mice. Binding was detectable but too low to be reliably quantified in the human cortex. Our results document Aβ-associated increases in 5-HT2BR mRNA expression and suggest reduced receptor binding in the context of AD. Studies investigating the functional involvement of microglial 5-HT2BRs in AD are considered relevant.

AB - Despite well-documented dysregulation in central serotonergic signaling in Alzheimer's disease (AD), knowledge about the potential involvement of the serotonin-2B receptor (5-HT2BR) subtype remains sparse. Here, we assessed the levels of 5-HT2BRs in brain tissue from APPswe/PS1dE9 transgenic (TG) mice, AD patients, and adult microglial cells. 5-HT2BR mRNA was measured by RT-qPCR in ageing TG and wild-type (WT) mice, in samples from the middle frontal gyrus of female, AD and control subjects, and in microglia from the cerebral cortex of WT mice. The density of 5-HT2BRs was measured by autoradiography using [3H]RS 127445. Both mouse and human brains had low levels of 5-HT2BR mRNA. In whole-brain mouse samples, mRNA expression was significantly lower in TG mice compared to WT at > 18 months of age. In the Aβ-plaque-burdened neocortex and hippocampus of old TG mice, however, levels of 5-HT2BR mRNA were two-fold higher over control, with similar elevations observed in the Aβ-plaque-burdened frontal cortex of human AD patients. 5-HT2BR mRNA expression varied widely in adult microglia and was higher compared to other cortical cell subtypes. In mice, specific [3H]RS-127445 binding in the cortex was first detected after 3 months of age. The density of 5-HT2BRs was low and overall reduced in TG, compared to WT mice. Binding was detectable but too low to be reliably quantified in the human cortex. Our results document Aβ-associated increases in 5-HT2BR mRNA expression and suggest reduced receptor binding in the context of AD. Studies investigating the functional involvement of microglial 5-HT2BRs in AD are considered relevant.

KW - 5-HT

KW - APP/PS1

KW - Alzheimer

KW - Autoradiography

KW - Microglia

KW - PCR

KW - Serotonin

UR - http://www.scopus.com/inward/record.url?scp=85208401025&partnerID=8YFLogxK

U2 - 10.1016/j.neulet.2024.138013

DO - 10.1016/j.neulet.2024.138013

M3 - Journal article

C2 - 39426582

SN - 0304-3940

VL - 844

JO - Neuroscience Letters

JF - Neuroscience Letters

M1 - 138013

ER -