Lithium Provides Broad Therapeutic Benefits in an Alzheimer’s Disease Mouse Model

Article type: Research Article

Authors: Wiseman, Alyssa L.^{b; c} | Briggs, Clark A.^b | Peritt, Ariel^{b; f} | Kapecki, Nicolas^b | Peterson, Daniel A.^{a; b; c} | Shim, Seong S.^{d; e; 1; *} | Stutzmann, Grace E.^{a; b; c}

Affiliations: [a] Center for Neurodegenerative Disease and Therapeutics, Rosalind Franklin University, North Chicago, IL, USA | [b] Discipline of Neuroscience, The Chicago Medical School, Rosalind Franklin University, North Chicago, IL, USA | [c] School of Graduate and Postdoctoral Studies, Rosalind Franklin University, North Chicago, IL, USA | [d] Discipline of Psychiatry and Behavioral Sciences, The Chicago Medical School, Rosalind Franklin University, North Chicago, IL, USA | [e] Captain James A. Lovell Federal Health Care Center, Mental Health, North Chicago, IL, USA | [f] Sackler School of Medicine, New York State/American Program of Tel Aviv University, Tel Aviv, Israel

Correspondence: [*] Correspondence to: Seong S. Shim MD, PhD, Mental Health Service Line (116A), Atlanta VA Medical Center, 1679 Clairmont Road, Decatur, GA 30096, USA. Tel.: +1 404 321 6111/Ext. 125254; E-mail:seong.shim@va.gov.

Note: [1] Present address: Emory University School of Medicine Department of Psychiatry and Behavioral Sciences, Mental Health Service Line, Atlanta VA Medical Center, Decatur, GA, USA.

Abstract: Background:Alzheimer’s disease (AD) is a chronic neurodegenerative disorder with a progressive loss of cognitive function. Currently, no effective treatment regimen is available. Lithium, a mood stabilizer for bipolar disorder, exerts broad neuroprotective and neurotrophic actions and improves cognitive function. Objective:The study investigated if lithium stabilizes Ca2+ signaling abnormalities in hippocampal neurons and subsequently normalize downstream effects on AD neuropathology and synaptic plasticity in young AD mice. Methods:Four-month-old 3xTg-AD mice were treated with a LiCl diet chow for 30 days. At the end of the lithium treatment, a combination of two-photon Ca2+ imaging, electrophysiology, and immunohistochemistry assays were used to assess the effects of the LiCl treatment on inositol trisphosphate receptor (IP3R)-dependent endoplasmic reticulum (ER) Ca2+ and voltage-gated Ca2+ channel (VGCC)-mediated Ca2+ signaling in CA1 neurons, neuronal nitric oxide synthase (nNOS) and hyperphosphorylated tau (p-tau) levels and synaptic plasticity in the hippocampus and overlying cortex from 3xTg-ADmice. Results:Thirty-day LiCl treatment reduced aberrant IP3R-dependent ER Ca2+ and VGCC-mediated Ca2+ signaling in CA1 pyramidal neurons from 3xTg-AD mice and restored neuronal nitric oxide synthase (nNOS) and hyperphosphorylated tau (p-tau) levels to control levels in the hippocampal subfields and overlying cortex. The LiCl treatment enhanced post-tetanic potentiation (PTP), a form of short-term plasticity in the hippocampus. Conclusion:The study found that lithium exerts therapeutic effects across several AD-associated early neuronal signaling abnormalities including aberrant Ca2+ signaling, nNOS, and p-tau formation and enhances short-term synaptic plasticity. Lithium could serve as an effective treatment or co-therapeutic for AD.

Keywords: Alzheimer’s disease, Ca²⁺signaling, lithium, neuronal nitric oxide synthase, phosphorylated tau, synaptic plasticity

DOI: 10.3233/JAD-220758

Journal: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 273-290, 2023