The Serotonergic System in Alzheimer's Disease

Serotonin, which is also called 5-hydroxytryptamine (5-HT), is a monoamine signaling molecule that functions as a tissue hormone, neurotransmitter, and neuromodulator. In the central nervous system, it is produced by a small cluster of neurons located in the raphe nuclei of the midbrain. These serotonergic neurons innervate numerous brain regions both rostrally and caudally. As a result, 5-HT modulates a range of physiological functions including circadian rhythms, mood, sleep, appetite, and learning and memory. Alzheimer’s disease (AD) has been associated with a decrease in the number of serotonergic neurons in the raphe nuclei, seemingly due to the accumulation of hyperphosphorylated Tau in this brain region. In addition, Amyloid beta (A-beta) deposits in the projection sites of serotonergic neurons can cause retrograde degeneration of these neurons. Moreover, research has also shown that the serotonergic system may actually contribute to the development and progression of AD. The 5-HT receptors 5-HT2A, 5-HT2C, and 5-HT4 can modulate the activity of several secretases, thereby affecting APP processing. Additionally, 5-HT4 has been shown to decrease A-beta production. It can directly interact with ADAM10, an alpha-secretase, and promote the non-amyloidogenic processing of APP. Furthermore, chronic activation of this receptor decreases BACE-1 expression. R&D Systems offers a range of research tools needed for investigating the role of the serotonergic system in AD.