Tau-A152T linked to AD induces neuronal hyperexcitation through FYN-NMDAR in human iPSC-neurons
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE225864 | GEO | 2024/12/31
REPOSITORIES: GEO
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Project description:Background:Episodic memory loss is a prominent clinical manifestation of Alzheimer's disease(AD), which is closely related to tau pathology and hippocampal impairment. Given the heterogeneity of brain neurons, the precise role of different brain neurons in terms of their sensitivity to tau accumulation and contribution to AD-like social memory loss remains unclear and requires further investigation. Methods: We investigated the effects of AD-like tau pathology by Tandem mass tag proteomic and phosphoproteomic experiments, social behavioral test, hippocampal electrophysiology, immunofluorescent staining and in vivo optical fiber recording of GCaMP6f and iGABASnFR. Additionally, we utilized optogenetics and administered ursolic acid (UA) via oral gavage to examine their effects on social memory in mice. Results: By proteomic and phosphoproteomic analyses, we identified the characteristics of ventral hippocampal CA1 (vCA1) under both physiological conditions and AD-like tau pathology. As tau progressively accumulated, not dorsal CA1 (dCA1), but vCA1, especially its excitatory and PV neurons, were fully filled with mislocated and phosphorylated tau. Overexpression of human Tau (hTau) in excitatory and PV neurons respectively mimicked AD-like tau accumulation, significantly inhibited the neuronal excitability and suppressed distinct discrimination-associated firings of these neurons within vCA1. Photoactivating excitatory and PV neurons in vCA1 at specific rhythm and time-window efficiently ameliorated tau-impaired social memory. Significantly, one-month administration of UA efficiently decreased tau accumulation via autophagy in a TFEB (transcription factor EB)-dependent manner and recovered vCA1 microcircuit to ameliorate tau-impaired social memory.Conclusion: This study elucidated distinct protein and phosphoprotein networks between dCA1 and vCA1, and highlighted the susceptibility of the vCA1 microcircuit to AD-like tau accumulation. Notably, our novel findings regarding the efficacy of UA in reducing tau load and targeting the vCA1 microcircuit may provide a promising strategy for AD treatment in the future.
2023-07-19 | PXD043883 |
Project description:Throughout life, neuronal networks in the mammalian neocortex maintain a balance of excitation and inhibition which is essential for neuronal computation. Deviations from a balanced state have been linked to neurodevelopmental disorders and severe disruptions result in epilepsy. To maintain balance, neuronal microcircuits composed of excitatory and inhibitory neurons sense alterations in neural activity and adjust neuronal connectivity and function. Here, we identified a signaling pathway in the adult mouse neocortex that is activated in response to elevated neuronal network activity. Over-activation of excitatory neurons is signaled to the network through the elevation of BMP2, a growth factor well-known for its role as morphogen in embryonic development. BMP2 acts on parvalbumin-expressing (PV) interneurons through the transcription factor SMAD1, which controls an array of glutamatergic synapse proteins and components of peri-neuronal nets. PV interneuron-specific disruption of BMP2-SMAD1 signaling is accompanied by a loss of PV cell glutamatergic innervation, underdeveloped peri-neuronal nets, and decreased excitability. Ultimately, this impairment of PV interneuron functional recruitment disrupts cortical excitation – inhibition balance with mice exhibiting spontaneous epileptic seizures. Our findings suggest that developmental morphogen signaling is re-purposed to stabilize cortical networks in the adult mammalian brain.
2024-02-16 | GSE255562 | GEO
Project description:Throughout life, neuronal networks in the mammalian neocortex maintain a balance of excitation and inhibition which is essential for neuronal computation. Deviations from a balanced state have been linked to neurodevelopmental disorders and severe disruptions result in epilepsy. To maintain balance, neuronal microcircuits composed of excitatory and inhibitory neurons sense alterations in neural activity and adjust neuronal connectivity and function. Here, we identified a signaling pathway in the adult mouse neocortex that is activated in response to elevated neuronal network activity. Over-activation of excitatory neurons is signaled to the network through the elevation of BMP2, a growth factor well-known for its role as morphogen in embryonic development. BMP2 acts on parvalbumin-expressing (PV) interneurons through the transcription factor SMAD1, which controls an array of glutamatergic synapse proteins and components of peri-neuronal nets. PV interneuron-specific disruption of BMP2-SMAD1 signaling is accompanied by a loss of PV cell glutamatergic innervation, underdeveloped peri-neuronal nets, and decreased excitability. Ultimately, this impairment of PV interneuron functional recruitment disrupts cortical excitation – inhibition balance with mice exhibiting spontaneous epileptic seizures. Our findings suggest that developmental morphogen signaling is re-purposed to stabilize cortical networks in the adult mammalian brain.
2024-02-16 | GSE255587 | GEO
Project description:Throughout life, neuronal networks in the mammalian neocortex maintain a balance of excitation and inhibition which is essential for neuronal computation. Deviations from a balanced state have been linked to neurodevelopmental disorders and severe disruptions result in epilepsy. To maintain balance, neuronal microcircuits composed of excitatory and inhibitory neurons sense alterations in neural activity and adjust neuronal connectivity and function. Here, we identified a signaling pathway in the adult mouse neocortex that is activated in response to elevated neuronal network activity. Over-activation of excitatory neurons is signaled to the network through the elevation of BMP2, a growth factor well-known for its role as morphogen in embryonic development. BMP2 acts on parvalbumin-expressing (PV) interneurons through the transcription factor SMAD1, which controls an array of glutamatergic synapse proteins and components of peri-neuronal nets. PV interneuron-specific disruption of BMP2-SMAD1 signaling is accompanied by a loss of PV cell glutamatergic innervation, underdeveloped peri-neuronal nets, and decreased excitability. Ultimately, this impairment of PV interneuron functional recruitment disrupts cortical excitation – inhibition balance with mice exhibiting spontaneous epileptic seizures. Our findings suggest that developmental morphogen signaling is re-purposed to stabilize cortical networks in the adult mammalian brain.
2024-02-16 | GSE255563 | GEO
Project description:Throughout life, neuronal networks in the mammalian neocortex maintain a balance of excitation and inhibition which is essential for neuronal computation. Deviations from a balanced state have been linked to neurodevelopmental disorders and severe disruptions result in epilepsy. To maintain balance, neuronal microcircuits composed of excitatory and inhibitory neurons sense alterations in neural activity and adjust neuronal connectivity and function. Here, we identified a signaling pathway in the adult mouse neocortex that is activated in response to elevated neuronal network activity. Over-activation of excitatory neurons is signaled to the network through the elevation of BMP2, a growth factor well-known for its role as morphogen in embryonic development. BMP2 acts on parvalbumin-expressing (PV) interneurons through the transcription factor SMAD1, which controls an array of glutamatergic synapse proteins and components of peri-neuronal nets. PV interneuron-specific disruption of BMP2-SMAD1 signaling is accompanied by a loss of PV cell glutamatergic innervation, underdeveloped peri-neuronal nets, and decreased excitability. Ultimately, this impairment of PV interneuron functional recruitment disrupts cortical excitation – inhibition balance with mice exhibiting spontaneous epileptic seizures. Our findings suggest that developmental morphogen signaling is re-purposed to stabilize cortical networks in the adult mammalian brain.
2024-02-16 | GSE255466 | GEO
Project description:Disease causal mechanism remains largely unknown for most Alzheimer’s disease (AD) genome-wide association studies (GWAS) risk loci, including the Clusterin (CLU) locus. Here, leveraging our approach to identify functional GWAS risk variants that show allele-specific open chromatin (ASoC), we nominated a putative AD causal SNP rs1532278 (T/C) of CLU that showed strong ASoC specifically in iPSC-derived excitatory neurons (iGlut). We found the AD protective allele T of rs1532278 elevated neuronal CLU and promoted neuron excitability. Transcriptomic analysis of iGlut (T/T vs. C/C) co-cultured with mouse astrocytes surprisingly showed allele T upregulated lipid synthesis and astrocytic lipid metabolism pathways. Further corroborative functional studies mechanistically tied allele T to CLU-facilitated neuron-glia lipid transfer and astrocytic lipid droplet (LD) formation. Interestingly, astrocytes with more LD were found to uptake less glutamate likely due to reactive oxygen species (ROS), which may contribute to CLU-promoted neuron excitability. Our study uncovered a previously unappreciated protective role of neuronal CLU in maintaining proper neuronal excitability through lipid-mediated neuron-glia communication.
2024-06-10 | GSE269153 | GEO
Project description:Selective neurodegeneration is a critical causal factor in Alzheimer’s disease (AD); however, the mechanisms that lead some neurons to perish while others remain resilient are unknown. We sought potential drivers of this selective vulnerability using single-nucleus RNA sequencing and discovered that apoE expression level is a substantial driver of neuronal variability. Strikingly, neuronal expression of apoE—which has a robust genetic linkage to AD—correlated strongly, on a cell-by-cell basis, with immune response pathways in neurons in the brains of wildtype mice, human apoE knock-in mice, and humans with or without AD. Elimination or over-expression of neuronal apoE revealed a causal relationship between apoE expression, neuronal MHC-I expression, Tau pathology, and neurodegeneration. Functional reduction of MHC-I ameliorated Tau pathology in apoE4-expressing primary neurons and in mouse hippocampi expressing pathological Tau. These findings suggest a mechanism linking neuronal apoE expression to MHC-I expression and, subsequently, to Tau pathology and selective neurodegeneration.
2021-04-19 | GSE167497 | GEO
Project description:Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to lack of appropriate human models. Here, we engineered new human induced pluripotent stem cell (hiPSC)-derived neuronal lines to express 4R Tau and 4R Tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes including shared transcriptomic signatures, autophagic body accumulation, and reduced neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of seeding-induced Tau propagation, including retromer VPS29 and genes in the UFMylation cascade. In progressive supranuclear palsy (PSP) and Alzheimer’s Disease (AD) brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade in vitro and in vivo suppressed seeding-induced Tau propagation. This model provides a robust platform to identify novel therapeutic strategies for 4R tauopathy.
2024-04-08 | GSE255904 | GEO
Project description:Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to lack of appropriate human models. Here, we engineered new human induced pluripotent stem cell (hiPSC)-derived neuronal lines to express 4R Tau and 4R Tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes including shared transcriptomic signatures, autophagic body accumulation, and reduced neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of seeding-induced Tau propagation, including retromer VPS29 and genes in the UFMylation cascade. In progressive supranuclear palsy (PSP) and Alzheimer’s Disease (AD) brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade in vitro and in vivo suppressed seeding-induced Tau propagation. This model provides a robust platform to identify novel therapeutic strategies for 4R tauopathy.
2024-04-08 | GSE255902 | GEO
Project description:INTRODUCTION Alzheimer’s disease (AD) is an advanced neurodegenerative disorder characterized by progressive impairment in both memory loss and cognitive capacities, which resulting in severe dementia [1]. The pathogenesis of AD is complicated and poorly understood. According to the World Alzheimer Report 2018, it is estimated that AD affects at least 50 million persons throughout the world, and the number of people with AD will double nearly every 20 years [2]. Over the past decade, various theories have been developed for the neuropathological level of AD, but the most popular distinct pathological hallmarks is extracellular accumulation of amyloid beta (Aβ) plaques, as well as the neurofibrillary tangles (NFTs) composed of the hyperphosphorylated tau in the form of in the select brain regions [3]. The other factors including mitochondrial dysfunction, oxidative stress, brain inflammation and neurotransmitter disturbances pathology have been recognized as a contributing factor in the pathogenesis of AD [4]. To date, only symptomatic therapies are available for AD patients. Cholinesterase inhibitors (CIs) are approved for mild to moderate AD patients, and memantine is the only one N-methyl-D-aspartate receptor (NMDAR) antagonist has been approved for moderate to severe AD [5]. NMDAR is a glutamate ionotropic receptor, they display high Ca2+ permeability and voltage-dependent block by Mg2+[6]. In AD patients, NMDARs could be overactivated due to increasing glutamate release from presynaptic neurons. Overactived NMDARs lead first to Ca2+ overload in postsynaptic neurons, followed by desensitization and internalization, resulting in synaptic dysfunction and ultimately cell death [7, 8]. The numerous factors than can influence the levels of endogenous glutamate release in the pathogenesis of AD, deposition of Aβplaques, soluble Aβoligomers, NFTs, mitochondrial dysfunction and oxidative stress have been associated with the higher concentration of glutamate release[9, 10]. Memantine is an uncompetitive, moderate affinity NMDA receptor (NMDAR) antagonist which is used for a further therapeutic option of moderate to severe AD [5]. Its effects have been investigated in a large number of in vitro and in vivo studies, which indicated that memantine can against Aβ-induced glutamate-mediated toxicity, attenuate phosphorylation of tau and reduces level of total precursor protein (APP) in human neuroblastoma SK-N-SH cells [11], and lower Aβ1-42 secretion and plaques in primary cortical neuronal culture cells [9, 12]. Some studies showed that memantine also completely protected against Aβ-induced ROS injure in the primary hippocampal neurons [13]. Studies with transgenic animal models showed that memantine reduced the levels of soluble Aβ1-42, Aβ plaque deposition and lowered the loss of synaptic density in APP/PS1mice [4, 14, 15], and decreased the levels of total tau and hyperphosphorylated tau in 3×Tg-AD mice [3]. Furthermore, memantine altered genes expression in adult rat brain [16], and modulated protein profiles in Down syndrome mice brain [17]. However, no comprehensive study of proteomic characteristics description of 3×Tg-AD transgenic mice under the memantine treatment has been conducted to date as far as we searched. In order to better understand the multiple actions of memantine, we conducted detailed analysis of proteomics and bioinformatics to dissect the molecular mechanisms of memantine for the treatment of AD.
2019-11-12 | PXD012110 | Pride