TY - JOUR

T1 - Plaque deposition dependent decrease in 5-HT2A serotonin receptor in AbetaPPswe/PS1dE9 amyloid overexpressing mice

AU - Holm, Peter

AU - Ettrup, Anders

AU - Klein, Anders B

AU - Santini, Martin A

AU - El-Sayed, Mona

AU - Elvang, Anders B

AU - Stensbøl, Tine B

AU - Mikkelsen, Jens D

AU - Knudsen, Gitte M

AU - Kleijn, Susana Aznar

PY - 2010/1/1

Y1 - 2010/1/1

N2 - Intrahippocampal injections of aggregated amyloid-beta (Abeta)1-42 in rats result in memory impairment and in reduction of hippocampal 5-HT2A receptor levels. In order to investigate how changes in 5-HT2A levels and functionality relate to the progressive accumulation of Abeta protein, we studied 5-HT2A receptor regulation in double transgenic AbetaPPswe/PS1dE9 mice which display excess production of Abeta and age-dependent increase in amyloid plaques. Three different age-groups, 4-month-old, 8- month-old, and 11-month-old were included in the study. [3H]-MDL100907, [3H]-escitalopram, and [11C]-PIB autoradiography was performed for measuring 5-HT2A receptor, serotonin transporter (SERT), and Abeta plaque levels in medial prefrontal cortex (mPFC), prefrontal cortex (PFC), frontoparietal cortex (FPC), dorsal and ventral hippocampus, and somatosensory cortex. To investigate 5-HT2A receptor functionality, animals were treated with the 5-HT2A receptor agonist DOI and head-twitch response (HTR) subsequently recorded. Expression level of the immediate early gene c-fos was measured by in situ hybridization. We found that the age-related increase in Abeta plaque burden was accompanied by a significant decrease in 5-HT2A receptor binding in mPFC in the 11-month-old group. The changes in 5-HT2A receptor binding correlated negatively with [11C]-PIB binding and were not accompanied by decreases in SERT binding. Correspondingly, 11-month-old transgenic mice showed diminished DOI-induced HTR and reduced increase in expression of c-fos mRNA in mPFC and FPC. These observations point towards a direct association between Abeta accumulation and changes in 5-HT2A receptor expression that is independent of upstream changes in the serotonergic system.

AB - Intrahippocampal injections of aggregated amyloid-beta (Abeta)1-42 in rats result in memory impairment and in reduction of hippocampal 5-HT2A receptor levels. In order to investigate how changes in 5-HT2A levels and functionality relate to the progressive accumulation of Abeta protein, we studied 5-HT2A receptor regulation in double transgenic AbetaPPswe/PS1dE9 mice which display excess production of Abeta and age-dependent increase in amyloid plaques. Three different age-groups, 4-month-old, 8- month-old, and 11-month-old were included in the study. [3H]-MDL100907, [3H]-escitalopram, and [11C]-PIB autoradiography was performed for measuring 5-HT2A receptor, serotonin transporter (SERT), and Abeta plaque levels in medial prefrontal cortex (mPFC), prefrontal cortex (PFC), frontoparietal cortex (FPC), dorsal and ventral hippocampus, and somatosensory cortex. To investigate 5-HT2A receptor functionality, animals were treated with the 5-HT2A receptor agonist DOI and head-twitch response (HTR) subsequently recorded. Expression level of the immediate early gene c-fos was measured by in situ hybridization. We found that the age-related increase in Abeta plaque burden was accompanied by a significant decrease in 5-HT2A receptor binding in mPFC in the 11-month-old group. The changes in 5-HT2A receptor binding correlated negatively with [11C]-PIB binding and were not accompanied by decreases in SERT binding. Correspondingly, 11-month-old transgenic mice showed diminished DOI-induced HTR and reduced increase in expression of c-fos mRNA in mPFC and FPC. These observations point towards a direct association between Abeta accumulation and changes in 5-HT2A receptor expression that is independent of upstream changes in the serotonergic system.

KW - Aging

KW - Amphetamines

KW - Amyloid beta-Protein Precursor

KW - Aniline Compounds

KW - Animals

KW - Autoradiography

KW - Citalopram

KW - Data Interpretation, Statistical

KW - Fluorobenzenes

KW - Genes, fos

KW - Head Movements

KW - Humans

KW - In Situ Hybridization

KW - Indicators and Reagents

KW - Male

KW - Mice

KW - Mice, Transgenic

KW - Piperidines

KW - Plaque, Amyloid

KW - Receptor, Serotonin, 5-HT2A

KW - Serotonin Antagonists

KW - Serotonin Receptor Agonists

KW - Serotonin Uptake Inhibitors

KW - Thiazoles

U2 - 10.3233/JAD-2010-100117

DO - 10.3233/JAD-2010-100117

M3 - Journal article

C2 - 20413853

VL - 20

SP - 1201

EP - 1213

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

SN - 1387-2877

IS - 4

ER -