N, N-dimethyltryptamine, a natural hallucinogen, protects against Alzheimer's disease via modulating calcium-mediated intracellular signaling, sigma-1 receptor-mediated endoplasmic reticulum-mitochondria crosstalk, and neurogenesis

Abstract

Although various pharmacological drugs have been developed for the treatment of Alzheimer’s disease (AD), the outcomes are highly unsatisfactory. Recent research showed that psychedelics promote neuroplasticity, stimulate neurogenesis, and reduce neuroinflammation, suggesting their possible therapeutic role in a variety of psychiatric and neurological disorders. This inevitably makes them promising candidates for the therapy in AD.

N,N-dimethyltryptamine (DMT), a natural psychedelic, has demonstrated anti-inflammatory and neuroprotective properties. Hence, we hypothesized that DMT might ameliorate cognitive impairment in AD. The acute effect with a single high dose and the chronic effect with a repeated micro-dose of DMT administration and the related action mechanisms were evaluated in this study. 5×FAD and 3×TG-AD transgenic mice received one single injection of 6 or 12 mg/kg DMT and were tested at 0.5 and 2 hours thereafter in a Y-maze for spatial memory. DMT at 12 mg/kg partially or completely reversed the behavioral indices at multiple time points, up to 2 hours post injection. The rapid-onset behavioral improvement was consistent with pharmacokinetic analysis of DMT, showing approximately 30 min to reach the maximum concentration in the brain tissue. DMT potently enhanced hippocampal long-term potentiation (LTP) and mobilized intracellular calcium activity, expression, and phosphorylation of calcium/calmodulin-dependent protein kinase II and AMPA-type glutamate receptor 1, the two key calcium-activated mediators involved in LTP induction. DMT also rapidly increased adenosine triphosphate (ATP) dynamics in in vivo and in vitro models. These results suggest that DMT may act as a fast-acting nootropic agent for treating AD in particular wandering.

Then, 3×TG-AD mice and Aβ25-35 -injected mice received intraperitoneal injections of 2 mg/kg DMT for 3 weeks to determine the effect of DMT on cognition. In water maze test, DMT reversed the striking decrease in the behavioral parameters of mice, time in platform and target quadrant. DMT also effectively abolished Aβ deposits of the 3×TG-AD mice brain. DMT modulated endoplasmic reticulum (ER)-mitochondrial crosstalk in the in vivo and in vitro models of AD, including the distance, contact points, and calcium homeostasis between ER and mitochondria. Additionally, DMT protected mitochondrial structure and functions in the hippocampal neurons, facilitated the tricarboxylic acid cycle and improved mitochondrial membrane potentiation and ATP production. Moreover, study results suggested that Sig-1r activation might contribute to the modulation of ER-mitochondria crosstalk by DMT.

To further investigate the effect of DMT on the neurogenesis in AD, 3×TG-AD mice and Aβ25-35 -injected mice were administrated with 2 mg/kg DMT for 3 weeks, and the primary hippocampal neurons were exposed to Aβ25-35 plaque in the presence or absence of DMT. Results showed that DMT promoted hippocampal neurogenesis in both in vivo and in vitro models of AD by promoting the proliferation of neural stem cells and inducing neural differentiation in the subgranular zone and granule cell layer of the hippocampus. Moreover, DMT improved hippocampal synaptic plasticity in the hippocampus of Aβ-injected mice. Sig-1r is essential for the DMT-promoted hippocampal neurogenesis. Taken together, DMT is a potential candidate to protect against AD. It provides a novel therapeutic target for AD treatment.