Differential modulation of amyloid‐beta levels by psychotropic medications in an in vitro model of Alzheimer’s disease

Abstract

AbstractBackgroundPreclinical studies suggest that psychotropic drugs (e.g. antidepressants, benzodiazepines) can affect amyloid‐β (Aβ) levels, yet mechanisms remain unclear. We aimed to determine the effects of common psychiatric drugs on Aβ generation and clearance in an in vitro model of Alzheimer’s disease (AD).MethodThe effects of a range of psychotropic drugs on Aβ generation and clearance were assessed in N2a/APP695swe cells, a neuroblastoma cell line overexpressing APP with the Swedish mutation. Cells were incubated for 24h with either fluoxetine (selective serotonin reuptake inhibitor (SSRI); 1‐10μM), venlafaxine (serotonin‐norepinephrine reuptake inhibitor (SNRI); 0.1‐10μM), mirtazapine (α2‐adrenergic antagonist; 1‐25μM), phenelzine (monoamine oxidase inhibitor (MAOI); 10‐50μM) or nordiazepam (benzodiazepine (BNZ); 1‐25μM). Aβ42 levels were quantified in conditioned media using an enzyme‐linked immunosorbent assay (ELISA). Amyloid precursor protein (APP) processing was studied using western blots (WBs), including expression of different secretases, full‐length APP, C‐terminal fragments (CTFs) in membrane preps and APP soluble‐α in media. Neprilysin and insulin degrading enzyme (IDE) expression was quantified as major Aβ clearance factors.ResultsCertain drugs increased Aβ levels; in particular, Venlafaxine (SNRI) and nordiazepam (BNZ) elevated Aβ42 at 10 µM, due to increased amyloidogenic APP cleavage. Conversely, the anti‐depressant drug fluoxetine (SSRI; 10 µM) reduced Aβ42, concomitant with reduced β‐secretase (BACE1) and presenilin‐2 expressions. Mirtazapine (α2‐adrenergic antagonist) and phenelzine (MAOI), on the other hand, did not modulate Aβ levels.ConclusionCertain psychotropic medications, i.e. nordiazepam (BNZ) and venlafaxine (SNRI) can increase Aβ levels, while fluoxetine (SSRI) can reduce them. This results from the effects of these drugs on Aβ generation rather than clearance. This is important, as the administration of these drugs could affect AD‐risk.