Lithium Deficiency and the Onset of Alzheimer’s Disease
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE275326 | GEO | 2025/06/12
REPOSITORIES: GEO
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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 | GSE295788 | GEO
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:Aging leads to a progressive deterioration in brain function, which will eventually result in cognitive decline and can develop into a dementia. The mechanisms underlying pathological cognitive decline in aging are still poorly understood. The peripheral immune system, as well as the meningeal lymphatic vasculature and the immune cells residing in the brain and meninges, are all affected by aging. Moreover, recent studies have linked the dysfunction of the meningeal lymphatic system and peripheral immunity to accelerated brain aging. We hypothesized that an age-related reduction in CCR7-dependent immune cell egress through the lymphatic vasculature mediates some aspects of aging-associated brain dysfunction, leading to cognitive decline and potentially exacerbating neurodegenerative diseases. Here, we report a reduction in CCR7 expression by meningeal T cells in aged mice and its associated increase in meningeal T-regulatory cells. Hematopoietic CCR7 deficiency mimicked the aging-associated changes in meningeal T cells and led to cognitive impairment. Interestingly, CCR7-deficient mice also presented impaired brain glymphatic function and showed increased amyloid beta (A) deposition when crossed with the 5xFAD transgenic mouse model of Alzheimer’s disease (AD). These results show that the aging-associated decrease in CCR7 expression impacts meningeal immunity, affects different aspects of brain function and exacerbates brain A pathology, highlighting its potential as a pathogenic mechanism for cognitive decline in aging and AD.
2021-03-22 | GSE163725 | GEO
Project description:The decline of cognitive function is a feature of normal human aging and is exacerbated in AlzheimerM-bM-^@M-^Ys disease (AD). DNA repair declines in brain cells during normal aging and even more so in AD. Here we show that experimental reduction in levels of the base excision repair enzyme, DNA polymerase M-NM-2 (Polb) renders neurons vulnerable to age-related dysfunction and degeneration in a mouse model of AD. Whereas 3xTgAD mice exhibit age-related extracellular amyloid b-peptide (Ab) accumulation and cognitive deficits, but no neuronal death, 3xTg/Polb+/- mice accumulates intracellular Ab and neurons die in the hippocampus and cerebral cortex. The DNA repair-deficient 3xTgAD mice exhibited increased DNA strand breaks and apoptotic caspase activation with loss of hippocampal volume, and impaired synaptic plasticity and memory retention. Molecular profiling revealed remarkable similarities in gene expression alterations in brain cells of AD patients and 3xTgAD/Polb+/- mice including multiple abnormalities suggestive of impaired cellular bioenergetics. Our findings demonstrate that a modest decrement in oxidative DNA damage processing is sufficient to render neurons vulnerable to AD-related pathogenic molecular and cellular alterations that result in the dysfunction and death of neurons, and associated cognitive deficits. 4 mouse strains were used in these experiments, the 3xTgAD and Pol M-NM-2 (+/-) mice were bred at the National Institute on Aging (Baltimore, Maryland). The original line 3xTgAD line was generated as described previously (Oddo, et. al 2003) and possess APPswe, PS1M146V, and tauP301L mutations. DNA polymerase beta heterozygous mice, Pol M-NM-2 (+/-), were crossed with the 3xTgAD mice to generate a 3xTgAD/Pol M-NM-2 (+/-) mouse. The Wt strain is C57Bl/6. At 20 months of age these mice were euthanized by cervical dislocation, the brain removed from the skull and dissected into regions of interest, the prefrontal cortex was used for the microarray studies.
2015-01-05 | E-GEOD-60911 | biostudies-arrayexpress
Project description:Aging and increased amyloid burden are major risk factors for cognitive diseases such as Alzheimer's Disease (AD). An effective therapy does not yet exist. Here we use mouse models for age-associated memory impairment and amyloid deposition to study transcriptome and cell type-specific epigenome plasticity at the systems level in the brain and in peripheral organs. We show that at the level of epigenetic gene-expression aging and amyloid pathology are associated with inflammation and impaired synaptic function in the hippocampal CA1 region. While inflammation is associated with increased gene-expression that is linked to a subset of transcription factors, de-regulation of plasticity genes is mediated via different mechanisms in the amyloid and the aging model. Amyloid pathology impairs histone-acetylation and decreases expression of plasticity genes while aging affects differential splicing that is linked to altered H4K12 acetylation at the intron-exon junction in neurons but not in non-neuronal cells. We furthermore show that oral administration of the clinically approved histone deacetylase inhibitor Vorinostat not only restores spatial memory, but also exhibits an anti-inflammatory action and reinstates epigenetic balance and transcriptional homeostasis at the level of gene expression and exon usage. This is the first systems-level investigation of transcriptome plasticity in the hippocampal CA1 region in aging and AD models and of the effects of an orally dosed histone deacetylase inhibitor. Our data has important implications for the development of minimally invasive and cost-effective therapeutic strategies against age-associated cognitive decline. In fact, our data strongly suggest to test Vorinostat in patients suffering from AD.
2015-08-17 | GSE63944 | GEO
Project description:Aging and increased amyloid burden are major risk factors for cognitive diseases such as Alzheimer's Disease (AD). An effective therapy does not yet exist. Here we use mouse models for age-associated memory impairment and amyloid deposition to study transcriptome and cell type-specific epigenome plasticity at the systems level in the brain and in peripheral organs. We show that at the level of epigenetic gene-expression aging and amyloid pathology are associated with inflammation and impaired synaptic function in the hippocampal CA1 region. While inflammation is associated with increased gene-expression that is linked to a subset of transcription factors, de-regulation of plasticity genes is mediated via different mechanisms in the amyloid and the aging model. Amyloid pathology impairs histone-acetylation and decreases expression of plasticity genes while aging affects differential splicing that is linked to altered H4K12 acetylation at the intron-exon junction in neurons but not in non-neuronal cells. We furthermore show that oral administration of the clinically approved histone deacetylase inhibitor Vorinostat not only restores spatial memory, but also exhibits an anti-inflammatory action and reinstates epigenetic balance and transcriptional homeostasis at the level of gene expression and exon usage. This is the first systems-level investigation of transcriptome plasticity in the hippocampal CA1 region in aging and AD models and of the effects of an orally dosed histone deacetylase inhibitor. Our data has important implications for the development of minimally invasive and cost-effective therapeutic strategies against age-associated cognitive decline. In fact, our data strongly suggest to test Vorinostat in patients suffering from AD.
2015-08-17 | GSE63943 | GEO
Project description:Aging and increased amyloid burden are major risk factors for cognitive diseases such as Alzheimer's Disease (AD). An effective therapy does not yet exist. Here we use mouse models for age-associated memory impairment and amyloid deposition to study transcriptome and cell type-specific epigenome plasticity at the systems level in the brain and in peripheral organs. We show that at the level of epigenetic gene-expression aging and amyloid pathology are associated with inflammation and impaired synaptic function in the hippocampal CA1 region. While inflammation is associated with increased gene-expression that is linked to a subset of transcription factors, de-regulation of plasticity genes is mediated via different mechanisms in the amyloid and the aging model. Amyloid pathology impairs histone-acetylation and decreases expression of plasticity genes while aging affects differential splicing that is linked to altered H4K12 acetylation at the intron-exon junction in neurons but not in non-neuronal cells. We furthermore show that oral administration of the clinically approved histone deacetylase inhibitor Vorinostat not only restores spatial memory, but also exhibits an anti-inflammatory action and reinstates epigenetic balance and transcriptional homeostasis at the level of gene expression and exon usage. This is the first systems-level investigation of transcriptome plasticity in the hippocampal CA1 region in aging and AD models and of the effects of an orally dosed histone deacetylase inhibitor. Our data has important implications for the development of minimally invasive and cost-effective therapeutic strategies against age-associated cognitive decline. In fact, our data strongly suggest to test Vorinostat in patients suffering from AD.
2015-08-17 | GSE63942 | GEO
Project description:Unravel the mechanisms underlying brain aging and Alzheimer´s disease (AD) has been difficult because of complexity of the networks that drive these aging-related changes. Analysis of the gene expression in the brain is a valuable tool to study the function of the brain under normal and pathological conditions. Gene microarray technology allows massively parallel analysis of most genes expressed in a tissue, and therefore is an important research tool that potentially can provide the investigative power needed to address the complexity of brain aging and neurodegenerative processes. One of the reasons that account for the resistance of AD pathogenesis to analysis is that clinically normal subjects may exhibit considerable AD pathology, blurring criteria for distinguishing subjects with normal aging or AD. Here, we analyzed hippocampal and cortex frontal gene expression from 32 subjects separated in individuals presenting, 1) both pathologic and clinical AD (definitive AD); 2) AD pathology and normal clinic (pathologic AD); 3) cognitive impairment, without AD pathology (others dementias); and 4) no cognitive impairment, without AD pathology (normal individuals). Our results show that based on gene expression profile these individuals we could verify similarity between the definitive AD group and the group that only had AD-type pathology (pathologic AD). Specimens of hippocampus and cortex frontal used in this study were obtained at autopsy from 32 subjects. Neuropathology, specifically NFT and NP, was assessed in accordance to the Braak staging and CERAD scores, respectively. Based on pathologic and clinic criteria, subjects were categorized into four groups: 1) nine subjects with AD neuropathologic (Braak = IV / V / VI and CERAD ≠ 0) presenting cognitive impairment (CDR ≥ 1), termed “definitive AD” (dAD); 2) five subjects with AD neuropathologic (Braak = IV / V / VI and CERAD ≠ 0) and without cognitive impairment (CDR = 0), termed “pathologic AD” (pAD); 3) nine subjects without AD neuropathologic (Braak = 0 / I / II and CERAD ≠ C) presenting cognitive impairment (CDR ≥ 1), termed “other dementias” (OD); 4) - nine subjects without AD neuropathologic (Braak = 0 / I / II and CERAD ≠ C) and without cognitive impairment (CDR = 0), termed “normal” (N). RNA isolation and Amplification. From total RNA, a two-round linear amplification procedure (T7-based protocol) was carried out for all samples and for a pool of RNAs obtained from 15 distinct human cell lines used as reference. Labeled cDNA was generated in a reverse transcriptase reaction using amplified RNA (aRNA). Equal amounts of test and reference cDNA reverse color Cy-labeled aRNA targets were competitively hybridized against the cDNA probes in a customized cDNA platform with 4,608 ORESTES representing human genes. Dye-swap was performed for each sample as control for dye bias and used as replicate.
2013-01-11 | E-GEOD-13214 | biostudies-arrayexpress
Project description:The decline of cognitive function is a feature of normal human aging and is exacerbated in Alzheimer’s disease (AD). DNA repair declines in brain cells during normal aging and even more so in AD. Here we show that experimental reduction in levels of the base excision repair enzyme, DNA polymerase β (Polb) renders neurons vulnerable to age-related dysfunction and degeneration in a mouse model of AD. Whereas 3xTgAD mice exhibit age-related extracellular amyloid b-peptide (Ab) accumulation and cognitive deficits, but no neuronal death, 3xTg/Polb+/- mice accumulates intracellular Ab and neurons die in the hippocampus and cerebral cortex. The DNA repair-deficient 3xTgAD mice exhibited increased DNA strand breaks and apoptotic caspase activation with loss of hippocampal volume, and impaired synaptic plasticity and memory retention. Molecular profiling revealed remarkable similarities in gene expression alterations in brain cells of AD patients and 3xTgAD/Polb+/- mice including multiple abnormalities suggestive of impaired cellular bioenergetics. Our findings demonstrate that a modest decrement in oxidative DNA damage processing is sufficient to render neurons vulnerable to AD-related pathogenic molecular and cellular alterations that result in the dysfunction and death of neurons, and associated cognitive deficits.
2015-01-05 | GSE60911 | GEO
Project description:The excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter in the brain expressed predominantly in astrocytes and at low levels in neurons and axonal terminals. EAAT2 expression is reduced in aging and sporadic Alzheimer’s disease (AD) patients’ brains. The role EAAT2 plays in cognitive aging and its associated mechanisms remains largely unknown. Here, we show that conditional deletion of astrocytic and neuronal EAAT2 results in age-related cognitive deficits. Astrocytic, but not neuronal EAAT2, deletion leads to early deficits in short-term memory and in spatial reference learning and long-term memory. Neuronal EAAT2 loss results in late-onset spatial reference long-term memory deficit. Neuronal EAAT2 deletion leads to dysregulation of the kynurenine pathway, and astrocytic EAAT2 deficiency results in dysfunction of innate and adaptive immune pathways, which correlate with cognitive decline. Astrocytic EAAT2 deficiency also shows transcriptomic overlaps with human aging and AD. Overall, the present study shows that in addition to the widely recognized astrocytic EAAT2, neuronal EAAT2 plays a role in hippocampus-dependent memory. Furthermore, the gene expression profiles associated with astrocytic and neuronal EAAT2 deletion are substantially different, with the former associated with inflammation and synaptic function similar to changes observed in human AD and gene expression changes associated with inflammation similar to the aging human brain.
2021-03-18 | GSE169083 | GEO