Redundant Gs-coupled serotonin receptors regulate amyloid-β metabolism in vivo.
The aggregation of amyloid-β (Aβ) into insoluble plaques is a hallmark pathology of Alzheimer's disease (AD). Previous work has shown increasing serotonin levels with selective serotonin re-uptake inhibitor (SSRI) compounds reduces Aβ in the brain interstitial fluid (ISF) in a mouse model of AD and in the cerebrospinal fluid of humans. We investigated which serotonin receptor (5-HTR) subtypes and downstream effectors were responsible for this reduction.



Agonists of 5-HT4R, 5-HT6R, and 5-HT7R significantly reduced ISF Aβ, but agonists of other receptor subtypes did not. Additionally, inhibition of Protein Kinase A (PKA) blocked the effects of citalopram, an SSRI, on ISF Aβ levels. Serotonin signaling does not appear to change gene expression to reduce Aβ levels in acute timeframes, but likely acts within the cytoplasm to increase α-secretase enzymatic activity. Broad pharmacological inhibition of putative α-secretases increased ISF Aβ and blocked the effects of citalopram.



In total, these studies map the major signaling components linking serotonin receptors to suppression of brain ISF Aβ. These results suggest the reduction in ISF Aβ is mediated by a select group of 5-HTRs and open future avenues for targeted therapy of AD.
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.|Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
Jonathan R
JR
Fisher
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.|Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
Clare E
CE
Wallace
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.|Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
Danielle L
DL
Tripoli
Departments of Psychiatry, Radiology, and Neurology, University of Pennsylvania, Philadelphia, PA, USA.
Yvette I
YI
Sheline
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA. cirritoj@neuro.wustl.edu.|Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA. cirritoj@neuro.wustl.edu.|Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA. cirritoj@neuro.wustl.edu.|Present Address: Washington University, Neurology, 660 South Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA. cirritoj@neuro.wustl.edu.
John R
JR
Cirrito
D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D058227:Amyloidogenic Proteins / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism*; D051379:Mice; D017551:Microdialysis / Q000379:methods; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D011985:Receptors, Serotonin / Q000378:metabolism*
D058227:Amyloidogenic Proteins; D011985:Receptors, Serotonin; D053829:Amyloid Precursor Protein Secretases; D019205:GTP-Binding Protein alpha Subunits, Gs
Alzheimer’s Disease; Microdialysis; PKA; SSRI; Serotonin receptor; beta-amyloid; α-secretase