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Lithium Deficiency and the Onset of Alzheimer’s Disease

ABSTRACT: The non-genetic causes of Alzheimer’s disease (AD) are poorly understood1-4. Here, we show that endogenous lithium (Li) is a dynamically regulated metal in the brain. Li uptake is the most significantly impaired of all metals analyzed in aged individuals with mild cognitive impairment (MCI) and AD, but not in aging individuals with normal cognitive function. In addition, lithium is sequestered by aggregated amyloid β-protein (Aβ) in human AD and AD mouse models, significantly reducing Li bioavailability. The loss of Li observed in human AD was recapitulated in AD mouse models by feeding a lithium-deficient diet. Loss of only 50% of endogenous brain Li resulted in markedly elevated Aβ deposition through a predominant effect on Aβ42, as well as elevated tau phosphorylation in neurofibrillary tangle-like structures. Li deficiency also resulted in synapse loss, oligodendrocyte and myelin loss, and microglia with impaired Aβ degradative capacity and a proinflammatory phenotype, as well as significantly accelerated memory loss. Diet-induced Li deficiency in aging wild-type mice also gave rise to elevated Aβ42 generation, synapse loss, proinflammatory astroglial and microglial responses, and accelerated memory loss. A major consequence of endogenous Li deficiency is activation of the tau kinase GSK3β. At the systems level, Li deficiency induced a state of neural hyperexcitation. To explore a new therapeutic approach to AD, we screened lithium salts and identified lithium orotate as a salt with low amyloid binding and high brain uptake. LiO prevents and reverses AD pathology and memory loss in AD mouse models and wild-type mice, and is approximately 100-fold more potent than the clinical standard Li carbonate. LiO did not show evidence of toxicity after treatment with a therapeutic dose for most of the adult mouse lifespan. Thus, Li deficiency may be an early molecular event in the ontogeny of AD with protean multisystem effects in the brain.

ORGANISM(S): Mus musculus

PROVIDER: GSE272344 | GEO | 2025/06/09

REPOSITORIES: GEO

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Project description:Krohn2011 - Cerebral amyloid-β proteostasis regulated by membrane transport protein ABCC1 This model is described in the article: Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice. Krohn M, Lange C, Hofrichter J, Scheffler K, Stenzel J, Steffen J, Schumacher T, Brüning T, Plath AS, Alfen F, Schmidt A, Winter F, Rateitschak K, Wree A, Gsponer J, Walker LC, Pahnke J. J. Clin. Invest. 2011 Oct; 121(10): 3924-3931 Abstract: In Alzheimer disease (AD), the intracerebral accumulation of amyloid-β (Aβ) peptides is a critical yet poorly understood process. Aβ clearance via the blood-brain barrier is reduced by approximately 30% in AD patients, but the underlying mechanisms remain elusive. ABC transporters have been implicated in the regulation of Aβ levels in the brain. Using a mouse model of AD in which the animals were further genetically modified to lack specific ABC transporters, here we have shown that the transporter ABCC1 has an important role in cerebral Aβ clearance and accumulation. Deficiency of ABCC1 substantially increased cerebral Aβ levels without altering the expression of most enzymes that would favor the production of Aβ from the Aβ precursor protein. In contrast, activation of ABCC1 using thiethylperazine (a drug approved by the FDA to relieve nausea and vomiting) markedly reduced Aβ load in a mouse model of AD expressing ABCC1 but not in such mice lacking ABCC1. Thus, by altering the temporal aggregation profile of Aβ, pharmacological activation of ABC transporters could impede the neurodegenerative cascade that culminates in the dementia of AD. This model is hosted on BioModels Database and identified by: BIOMD0000000618. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Lithium Deficiency and the Onset of Alzheimer’s Disease

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