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

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Peter Holm, Anders Ettrup, Anders B Klein, Martin A Santini, Mona El-Sayed, Anders B Elvang, Tine B Stensbøl, Jens D Mikkelsen, Gitte M Knudsen, Susana Aznar Kleijn

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.
Original languageEnglish
JournalJournal of Alzheimer's Disease
Volume20
Issue number4
Pages (from-to)1201-13
Number of pages13
ISSN1387-2877
DOIs
Publication statusPublished - 1 Jan 2010

    Research areas

  • Aging, Amphetamines, Amyloid beta-Protein Precursor, Aniline Compounds, Animals, Autoradiography, Citalopram, Data Interpretation, Statistical, Fluorobenzenes, Genes, fos, Head Movements, Humans, In Situ Hybridization, Indicators and Reagents, Male, Mice, Mice, Transgenic, Piperidines, Plaque, Amyloid, Receptor, Serotonin, 5-HT2A, Serotonin Antagonists, Serotonin Receptor Agonists, Serotonin Uptake Inhibitors, Thiazoles

ID: 34143073