N,N-DIMETHYLTRYPTAMINE, A NATURAL HALLUCINOGEN, AMELIORATES ALZHEIMER’ S DISEASE BY RESTORING NEURONAL SIGMA-1 RECEPTOR- MEDIATED ENDOPLASMIC RETICULUM-MITOCHONDRIA CROSSTALK

Abstract Background Aberrant neuronal Sigma-1 receptor (Sig-1r)-mediated signaling between the endoplasmic reticulum (ER) and mitochondria plays an essential role in neuronal cytopathology of Alzheimer’ s disease (AD). The natural hallucinogen N,N-dimethyltryptamine (DMT) is a Sig-1r agonist that may have the anti- AD potential by protecting neuronal ER-mitochondrial interplay. Aim and Objectives The purpose of this study was to systematically investigate the anti-AD effects of DMT and the association with its restoration of neuronal ER-mitochondria signaling. Methods Effects of chronic DMT (2 mg/kg) for 3 weeks on cognitive impairment and Aβ deposits were examined in 3× TG-AD transgenic mouse model of AD. The effects of DMT on the expression of Sig-1r and mitochondria-associated membranes (MAM)-associated proteins, physical contact, and calcium dynamic between ER and mitochondria were detected in in vitro and in vivo paradigms, with the utilization of Sig-1r knockdown mice and the Sig-1r antagonist BD1063. Results Chronic DMT markedly alleviated cognitive impairment in water maze of 3× TG-AD transgenic mice. In parallel, it largely diminished Aβ deposits in the hippocampus and prefrontal cortex. DMT restored the decreased Sig-1r levels of the transgenic and knockdown mice and in cultured hippocampal neurons co-treated with BD1063. DMT prevented physical contact and calcium dynamic between the two organelles in in vitro and in vivo pathological circumstances. The hallucinogen also reinstated the expression of multiple mitochondria-associated membrane (MAM)-associated proteins in 3× TG-AD mice. Discussion and Conclusions These results suggest that the anti-AD effects of DMT are associated with its protection of neuronal ER-mitochondria crosstalk via the Sig-1r activation. DMT may serve as a novel preventive and therapeutic agent against AD.