Sun Choi

 Introduction. Alzheimer’s Disease (AD) is a progressive, neurodegenerative disease primarily of the hippocampus that presents with memory loss and a decline in cognition.¹ It is thought that asymptomatic changes initially occur in the brain in the form of amyloid beta (Aβ) plaque formation and tau tangles, which lead to neuronal death and brain atrophy.² One-third of AD patients experience neuropsychiatric symptoms (NPS) and the prevalence of depression in dementia ranges from 16% to 45%.³ The relationship between AD and depression is incompletely understood however, depressive symptoms and dementia may be due to neurobiological changes in common brain areas. BDNF and the mTOR pathway may be key factors in the etiology of both AD and depression in AD.³ In humans, neuroprotective protein BDNF has been demonstrated to be downregulated in AD and dysfunctional activation of the mTOR pathway is known to promote Aβ aggregation.^4,5,6,7 Ketamine, a NMDA receptor antagonist, has been shown to reverse these dysfunctional pathways in mice.⁸ These findings suggest that Ketamine may be a potential therapeutic agent for depression in AD.  Methods. Mice models were treated with soluble Aβ and tested for levels of BDNF in control mice, Aβ treated mice, and Aβ + Ketamine treated mice.⁹ Immobility was measured during the forced swim test.⁹ Post-mortem tissue analyses were performed on the prefrontal cortex using HPLC analysis.⁹ Levels of soluble Aβ and cortical NGF were quantified with ELISA. The study also tested the effects of fluoxetine and reboxetine.⁹ Results. Immobility frequency was significantly decreased in Aβ mice treated with ketamine compared to both the control and non-ketamine treated Aβ mice.⁹ Ketamine not only reversed the soluble Aβ-induced decrease of cortical BDNF, but also increased expression beyond the expression in control mice. However, ketamine had no effect on Aβ levels compared to the Aβ-induced mice without treatment.⁹  Discussion. In conclusion, ketamine shows promise as a potential therapeutic for depression in AD. Aβ Mice model studies have demonstrated that ketamine reverses decreased BDNF expression. However, ketamine also increases mTOR expression in non- Aβ induced mice⁸ Thus, future studies should explore if ketamine reverses the dysfunctional hyperactive mTOR expression in the setting of AD. In addition, further exploration of the underlying mechanism of ketamine and its effect on patients with depression in AD may shed light on the potential crosstalk between glutamate and inflammatory pathways in AD patients.

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