Affiliations: [a] Neuroscience Research Australia, Sydney, NSW, Australia
| [b] School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
| [c] The University of Sydney – Brain and Mind Centre, Sydney, NSW, Australia
| [d] School of Medicine, Western Sydney University, NSW, Australia
| [e] Illawarra Health and Medical Research Institute, University of Wollongong, NSW, Australia
| [f] School of Biological Sciences, University of Wollongong, NSW, Australia
Correspondence:
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Correspondence to: Associate Professor John B.J. Kwok, Brain and Mind Centre, Sydney Medical School, The University of Sydney, Camperdown, NSW 2050, Australia. Tel.: +61 2 9351 0807; E-mail: [email protected].
Note: [1] These authors contributed equally to this work.
Abstract: Alzheimer’s disease is characterized by abnormal amyloid-β (Aβ) peptide accumulation beginning decades before symptom onset. An effective prophylactic treatment aimed at arresting the amyloidogenic pathway would therefore need to be initiated prior to the occurrence of Aβ pathology. The SIGMAR1 gene encodes a molecular chaperone that modulates processing of the amyloid-β protein precursor (AβPP). Fluvoxamine is a selective serotonin reuptake inhibitor and a potent SIGMAR1 agonist. We therefore hypothesized that fluvoxamine treatment would reduce Aβ production and improve cognition. We firstly investigated the impact of SIGMAR1 on AβPP processing, and found that overexpression and knockdown of SIGMAR1 significantly affected γ-secretase activity in SK-N-MC neuronal cells. We then tested the impact of fluvoxamine on Aβ production in an amyloidogenic cell model, and found that fluvoxamine significantly reduced Aβ production by inhibiting γ-secretase activity. Finally, we assessed the efficacy of long-term treatment (i.e., ∼8 months) of 10 mg/kg/day fluvoxamine in the J20 amyloidogenic mouse model; the treatment was initiated prior to the occurrence of predicted Aβ pathology. Physical examination of the animals revealed no overt pathology or change in weight. We conducted a series of behavioral tests to assess learning and memory, and found that the fluvoxamine treatment significantly improved memory function as measured by novel object recognition task. Two other tests revealed no significant change in memory function. In conclusion, fluvoxamine has a clear impact on γ-secretase activity and AβPP processing to generate Aβ, and may have a protective effect on cognition in the J20 mice.
