Serotonergic Mechanisms in Alzheimer’s Disease Pathophysiology

Alzheimer’s disease (AD) involves progressive cognitive decline, neuropsychiatric symptoms and hallmark pathologies of amyloid-β accumulation and Tau hyperphosphorylation. The central serotonergic system, arising largely from the dorsal raphe nucleus, modulates neuronal excitability, synaptic plasticity and neuroinflammation. Alterations in serotonin (5-HT) release and receptor expression have been linked to imbalances in β-amyloid metabolism, dysregulation of Tau-kinase activity and impaired neurotrophic support. Diverse 5-HT receptor subtypes exert distinct influences: some promote amyloid precursor protein non-amyloidogenic processing, others facilitate kinase cascades that drive Tau phosphorylation. Beyond mood regulation, serotonergic signalling interfaces with cholinergic and neuroimmune pathways, shaping both prodromal behavioural changes and later cognitive deficits. Understanding these intertwined processes has highlighted new therapeutic avenues—from receptor-specific ligands to neuromodulatory interventions—that aim to restore serotonergic homeostasis and slow AD progression.

Research from Nature Portfolio

A study in an experimental Alzheimer model induced by D-galactose and ovariectomy demonstrated that treatment with the selective serotonin reuptake inhibitor escitalopram not only improved spatial memory but also attenuated core pathologies. Treated animals showed reductions in hippocampal amyloid-β42, β-secretase activity and phosphorylated Tau alongside increased α-secretase levels. Mechanistically, escitalopram modulated key intracellular cascades—enhancing PI3K/Akt/GSK-3β and Raf-1/MEK/ERK signalling while dampening JNK/c-Jun activation—thereby linking serotonergic enhancement to disease-modifying effects on both amyloid and Tau pathology.

Serotonergic Mechanisms in Alzheimer’s Disease Pathophysiology publication trend

The graph below shows the total number of articles in serotonergic mechanisms in alzheimer’s disease pathophysiology across all publications each year (not limited to Nature Index journals).

Technical terms

Serotonin (5-HT): A monoamine neurotransmitter involved in mood, cognition and neuroendocrine regulation.

5-HT receptor: A family of G-protein-coupled receptors and ligand-gated channels mediating diverse serotonin effects.

Amyloid-β (Aβ): Peptide fragments that aggregate to form extracellular plaques, central to AD pathology.

Tau hyperphosphorylation: Excessive addition of phosphate groups to Tau protein, leading to neurofibrillary tangle formation.

Cyclin-dependent kinase 5 (CDK5): A serine/threonine kinase that, when dysregulated, phosphorylates Tau and contributes to neuronal dysfunction.

Organoid: A three-dimensional cell culture model derived from stem cells that mimics aspects of human brain architecture and function.

References

1. iPSC-derived hindbrain organoids to evaluate escitalopram oxalate treatment responses targeting neuropsychiatric symptoms in Alzheimer’s disease. Molecular Psychiatry (2024).
2. Structural determinants for activation of the Tau kinase CDK5 by the serotonin receptor 5-HT7R. Cell Communication and Signaling (2024).
3. Amygdala neuronal dyshomeostasis via 5‐HT receptors mediates mood and cognitive defects in Alzheimer's disease. Aging Cell (2024).
4. Escitalopram Ameliorates Cognitive Impairment in D-Galactose-Injected Ovariectomized Rats: Modulation of JNK, GSK-3β, and ERK Signalling Pathways. Scientific Reports (2019).