Lithium Deficiency and the Onset of Alzheimer’s Disease
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1136488 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR29846342.fastq.gz | Fastqsanger.gz | |||
| SRR29846343.fastq.gz | Fastqsanger.gz | |||
| SRR29846346.fastq.gz | Fastqsanger.gz | |||
| SRR29846347.fastq.gz | Fastqsanger.gz |
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Project description:Lithium Deficiency and the Onset of Alzheimer’s Disease
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Project description:Lithium Deficiency and the Onset of Alzheimer’s Disease [3xTG_LiO]
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Project description: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.
2025-06-09 | GSE272344 | GEO
Project description:The earliest molecular changes in Alzheimer’s disease (AD) are poorly understood. Here we show that endogenous lithium (Li) is dynamically regulated in the brain and contributes to cognitive preservation during aging. We demonstrate that cortical uptake of Li is the most significantly impaired of all metals analyzed in mild cognitive impairment (MCI) and AD, and that Li bioavailability is further reduced by amyloid sequestration. Li deficiency was recapitulated by feeding AD model and wild-type mice a lithium-deficient diet. Reducing endogenous cortical Li by ~50% markedly elevated Aβ deposition and phospho-tau accumulation, and led to proinflammatory microglial activation, synapse loss, and accelerated cognitive decline. These effects were mediated, at least in part, through activation of the kinase GSK3β in neurons, microglia, and oligodendrocytes. Single nucleus RNA-seq showed that Li deficiency gives rise to significant transcriptome changes in all major brain cell types that overlap with transcriptome changes in AD. Replacement therapy with lithium orotate (LiO), a Li salt with reduced amyloid sequestration, prevents pathological changes and memory loss in AD mouse models and aging wild-type mice at a physiological concentration. Thus, Li deficiency may be among the earliest molecular events that link amyloid deposition to protean multisystem effects on the brain. Li replacement with amyloid-evading salts is a potentially novel therapeutic approach to AD and brain aging.
2025-06-12 | GSE275326 | GEO
Project description:The earliest molecular changes in Alzheimer’s disease (AD) are poorly understood. Here we show that endogenous lithium (Li) is dynamically regulated in the brain and contributes to cognitive preservation during aging. We demonstrate that cortical uptake of Li is the most significantly impaired of all metals analyzed in mild cognitive impairment (MCI) and AD, and that Li bioavailability is further reduced by amyloid sequestration. Li deficiency was recapitulated by feeding AD model and wild-type mice a lithium-deficient diet. Reducing endogenous cortical Li by ~50% markedly elevated Aβ deposition and phospho-tau accumulation, and led to proinflammatory microglial activation, synapse loss, and accelerated cognitive decline. These effects were mediated, at least in part, through activation of the kinase GSK3β in neurons, microglia, and oligodendrocytes. Single nucleus RNA-seq showed that Li deficiency gives rise to significant transcriptome changes in all major brain cell types that overlap with transcriptome changes in AD. Replacement therapy with lithium orotate (LiO), a Li salt with reduced amyloid sequestration, prevents pathological changes and memory loss in AD mouse models and aging wild-type mice at a physiological concentration. Thus, Li deficiency may be among the earliest molecular events that link amyloid deposition to protean multisystem effects on the brain. Li replacement with amyloid-evading salts is a potentially novel therapeutic approach to AD and brain aging.
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Project description:Alzheimer’s disease (AD) is the most common neurodegenerative dementia. Around 10% of cases present an age of onset before 65 years-old, which in turn can be divided in monogenic or familial AD (FAD) and sporadic early-onset AD (EOAD). Mutations in PSEN1, PSEN2 and APP genes have been linked with FAD. The aim of our study was to describe the brain whole-genome RNA expression profile of the posterior cingulate area in EOAD and FAD caused by PSEN1 mutations (FAD-PSEN1). 14 patients (7 EOAD and 7 FAD-PSEN1) and 7 neurologically healthy controls were selected and samples were hybridized in a Human Gene 1.1 microarray from Affymetrix. When comparing controls with EOAD and controls with FAD-PSEN1, we found 3183 and 3351 differentially expressed genes (DEG) respectively (FDR corrected p<0.05). However, any DEG was found in the comparison of the two groups of patients. Microarrays were validated through quantitative-PCR of 17 DEG. In silico analysis of the DEG revealed an alteration in biological pathways related to calcium-signaling, axon guidance and long-term potentiation (LTP), among others, in both groups of patients. These pathways are mainly related with cell signalling cascades, synaptic plasticity and learning and memory processes. In conclusion, the altered biological final pathways in EOAD and FAD-PSEN1 are highly coincident. Also, the findings are in line with those previously reported for late-onset AD (LOAD, onset >65 years-old), which implies that the consequences of the disease at the molecular level are similar in the final stages of the disease. 21 Samples were analyzed: 7 controls, 7 Early-onset Alzheimer's disease (AD) patients and 7 early-onset AD genetically determined by a mutation in PSEN1 gene.
2015-01-20 | E-GEOD-39420 | biostudies-arrayexpress
Project description:Non-familial Alzheimer’s disease (AD) occurring before 65 years of age is commonly referred to as early-onset Alzheimer’s disease (EOAD) and constitutes ~5-6% of all Alzheimer’s disease (AD) cases. While EOAD exhibits the same clinicopathological changes such as amyloid plaques, neurofibrillary tangles (NFTs), brain atrophy, and cognitive decline as observed in the more prevalent late-onset AD (LOAD), EOAD patients tend to have more severe cognitive deficits, including visuospatial, language, and motor dysfunction. Patient-derived induced pluripotent stem cells (iPSCs) have been used to model and study penetrative, familial AD (FAD) mutations in APP, PSEN1, and PSEN2, but have been seldom used for sporadic forms of AD that display more heterogeneous disease manifestation. In this study, we sought to characterize iPSC-derived neurons from EOAD patients via RNA-sequencing. A modest difference in expression profiles between EOAD patients and non-demented control subjects resulted in a limited number of differentially expressed genes (DEGs). Based on this analysis, we provide evidence that iPSC-derived neuron model systems, likely due to the loss of EOAD-associated epigenetic signatures during the iPSC reprogramming, are not an ideal model system to study sporadic AD.
2023-11-21 | GSE231341 | GEO
Project description:Modeling early-onset sporadic Alzheimer’s disease using iPSC-derived neurons
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Project description:Neuronal ABCA7 deficiency aggravates mitochondrial dysfunction and neurodegeneration in Alzheimer’s disease
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Project description:Pompe disease is a genetic disorder resulting from a deficiency of lysosomal acid alpha-glucosidase (GAA) that manifests as a clinical spectrum with regard to symptom severity and rate of progression. In this study, we used microarrays to examine gene expression from the muscle of two cohorts of infantile-onset Pompe patients to identify transcriptional differences that may contribute to the disease phenotype. We found strong similarities among the gene expression profiles generated from biceps and quadriceps, and identified a number of signaling pathways altered in both cohorts. We also found that infantile-onset Pompe patient muscle had a gene expression pattern characteristic of immature or regenerating muscle, and exhibited many transcriptional markers of inflammation, despite having few overt signs of inflammatory infiltrate. Further, we identified genes exhibiting correlation between expression at baseline and response to therapy. This combined dataset can serve as a foundation for biological discovery and biomarker development to improve the treatment of Pompe disease.
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