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Basic Science and Pathogenesis.

Mizuki Morisaki1,2, Oliver Milner2, William W Watts2

  • 1Cardiff university, Cardiff, Cardiff, United Kingdom.

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Antidepressants like mirtazapine and sertraline show potential in reducing dementia risk by protecting against amyloid beta toxicity. Further research is needed to confirm these promising findings for Alzheimer's disease prevention.

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Cell Biology

Background:

  • Depression is a known risk factor for Alzheimer's disease (AD) and other dementias.
  • The modifiability of this increased dementia risk through antidepressant intervention remains unclear.

Purpose of the Study:

  • To investigate the potential of antidepressant medications to mitigate dementia risk.
  • To examine the effects of sertraline and mirtazapine on neuronal health and function in cellular and acute brain slice models.

Main Methods:

  • Utilized SH-SY5Y and primary human hippocampal neurons treated with antidepressants or vehicle.
  • Exposed neurons to hypoxia or amyloid beta (Aβ) and assessed cell viability, mitochondrial health, and morphology.
  • Performed electrophysiological recordings in acute Wistar rat hippocampal slices to measure long-term potentiation (LTP).

Main Results:

  • Mirtazapine, but not sertraline, enhanced cell viability in differentiated SH-SY5Y neurons.
  • Sertraline reduced mitochondrial numbers and increased fragmentation, while mirtazapine increased mitochondrial elongation in response to Aβ.
  • Amyloid beta (Aβ) exposure increased mitochondrial numbers in neurons.
  • Sertraline (1µM) inhibited LTP in acute hippocampal slices; further experiments are ongoing.

Conclusions:

  • Preliminary findings suggest sertraline and mirtazapine may reduce dementia risk.
  • Potential mechanisms include reducing amyloid beta (Aβ) mitochondrial toxicity or excitotoxicity.