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

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.

The contribution of mitochondria-associated endoplasmic reticulum membranes (MAMs) dysfunction in Alzheimer’s disease and the potential countermeasure

“…Imatinib and imatinib methanesulfonate could prevent Aβ formation by inhibiting GSAP ( He et al, 2010 ; Weintraub et al, 2013 ; Chu et al, 2014 ). Lithium treatment reduced abnormal IP3R-dependent ER Ca 2+ signaling and enhanced synaptic plasticity in 3 × Tg AD mice ( Wiseman et al, 2023 ). Xestospongin C can ameliorate the Ca 2+ overload of primary hippocampal neurons induced by Aβ 1–42 and improve the cognitive ability of APP/PS1 mice ( Wang et al, 2019 ).…”

Diet and lifestyle impact the development and progression of Alzheimer’s dementia

“…Lithium treatment reduces p-tau and neurofibrillary tangles formation in animal models of tauopathies and AD (157)(158)(159). In addition, lithium treatment stabilized neuronal signaling alterations, including aberrant Ca 2+ signaling, restored neuronal nitric oxide synthase (nNOS) and p-tau levels, and enhanced short-term plasticity in the hippocampus of 3xTg-AD mice (160). Nevertheless, the evidence obtained in clinical trials is mixed.…”

Lithium: An Old Drug for New Therapeutic Strategy for Alzheimer’s Disease and Related Dementia

“…Most studies using APP transgenic AD mouse models have consistently reported that lithium reduces Aβ aggregation, senile plaques, phosphorylated tau (p-tau) formation, neurofibrillary tangles, and neuronal death and improves learning and working memory [28][29][30][31][32][33][34][35]. Studies using p-tau and p-tau/APP transgenic mouse models have also reported that lithium reduces Aβ aggregation, p-tau formation, and neurofibrillary tangles [9, [35][36][37][38]. These studies have suggested that the therapeutic effects of lithium are likely to be associated with its inhibition of glycogen synthase kinase (GSK) 3β [31-33, 35, 39].…”

“…In addition, future studies should consider nonconventional AD models, such as mice with deficiency of NMDA receptor subunit GluN3A, Table 2. The Effects of 30-day lithium treatment on aberrant Ca 2+ signaling, nNOS expression, tau phosphorylation, and synaptic plasticity in 3xTg-AD mice [38] 3xTg-AD mice Non-Tg mice lithium control lithium control which causes calcium dysregulation and AD-like behavioral phenotypes [92]. Moreover, it would be interesting to study the intricate relationships of cytosolic and ER calcium during pathogenesis of AD through recently developed, red-shifted calcium indicator protein for ER [137].…”

“…Our recent study has revealed that lithium stabilizes dysregulated Ca 2+ release via ER acting at IP 3 R. Specifically, subchronic lithium treatment normalizes aberrant IP 3 R-mediated ER Ca 2+ signaling in CA1 pyramidal cells in the hippocampus of 3xTg-AD mice. Interestingly, the same lithium treatment also reduces voltage-gated calcium channel (VGCC)-mediated Ca 2+ influx in the CA1 hippocampal neurons in the AD mice [38] (Table 2). These effects of lithium treatment on dysregulated Ca 2+ are largely associated with normalizing elevated neuronal nitric oxide (NO) synthase (nNOS) in the hippocampus and cortex in the 3xAD animal model.…”