Transcriptional vulnerability to amyloid-β and tau pathologies differentially disrupts emotional and memory neural circuits
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE279050 | GEO | 2025/02/07
REPOSITORIES: GEO
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Project description:Alzheimer’s disease (AD) is characterized by memory loss associated with accumulation of amyloid-β (Aβ) and tau in the brain, but how memory-processing neural circuits are differentially affected by each pathology remains unclear. Here, we investigated the transcriptional vulnerability to single and concomitant Aβ and tau pathologies in 6-month-old transgenic mice expressing mutant human amyloid precursor protein (APP), Tau, or both (APP/Tau mice) in excitatory neurons. We identified differential and synergistic pathology-induced transcriptional responses in the hippocampus of AD transgenic mice. These findings support the idea that Aβ and tau pathologies exert synergistic effects to disrupt gene expression programs underlying vulnerability of memory neural circuits in AD.
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Project description:The pathophysiology of Alzheimer’s disease (AD) is multifactorial with characteristic extracellular accumulation of amyloid-beta (Aβ) and intraneuronal aggregation of hyperphosphorylated tau in the brain. Development of disease-modifying treatment for AD has been challenging. Recent studies suggest that deleterious alterations in neurovascular cells happens in parallel with Aβ accumulation, inducing tau pathology and necroptosis. Therefore, therapies targeting cellular Aβ and tau pathologies may provide a more effective strategy of disease intervention. Tetramethylpyrazine nitrone (TBN) is a nitrone derivative of tetramethylpyrazine, an active ingredient from Ligusticum wallichii Franchat (Chuanxiong). We previously showed that TBN is a potent scavenger of free radicals with multi-targeted neuroprotective effects in rat and monkey models of ischemic stroke. The present study aimed to investigate the anti-AD properties of TBN. We employed AD-related cellular model (N2a/APPswe) and transgenic mouse model (3×Tg-AD mouse) for mechanistic and behavioral studies. Our results showed that TBN markedly improved cognitive functions and reduced Aβ and hyperphosphorylated tau levels in mouse model. Further investigation of the underlying mechanisms revealed that TBN promoted non amyloidogenic processing pathway of amyloid precursor protein (APP) in N2a/APPswe in vitro. Moreover, TBN preserved synapses from dendritic spine loss and upregulated synaptic protein expressions in 3×Tg-AD mice. Proteomic analysis of 3×Tg-AD mouse hippocampal and cortical tissues showed that TBN induced neuroprotective effects through modulating mitophagy, MAPK and mTOR pathways. In particular, TBN significantly upregulated PINK1, a key protein for mitochondrial homeostasis, implicating PINK1 as a potential therapeutic target for AD. In summary, TBN improved cognitive functions in AD-related mouse model, inhibited Aβ production and tau hyperphosphorylation, and rescued synaptic loss and neuronal damage. Multiple mechanisms underlie the anti-AD effects of TBN including the modulation of APP processing, mTOR signaling and PINK1-related mitophagy.
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Project description:Beyond deficits in hippocampal-dependent episodic memory, Alzheimer’s Disease (AD) features sensory impairment in visual cognition consistent with extensive neuropathology in the retina. 12A12 is a monoclonal cleavage specific antibody (mAb) which in vivo selectively neutralizes the AD-relevant, harmful N-terminal 20-22kDa tau fragment(s) (i.e NH2htau) without altering the full-length normal protein. When systemically-injected into Tg2576 mouse model overexpressing a mutant form of Amyloid Precursor Protein (APP), APPK670/671L linked to early-onset familial AD, this conformation-specific tau mAb successfully neutralizes the NH2htau accumulating both in their brain and retina and, thus, markedly alleviates the phenotype-associated signs. By means of combined biochemical and metabolic and transcriptomic experimental approach, we report that 12A12mAb downregulates the steady state expression levels of APP and Beta-Secretase 1 (BACE-1) and, thus, limits the Amyloid beta (Aβ) production both in hippocampus and retina from this AD animal model. The endocytic (BIN1, RIN3) and bioenergetic (glycolisis and mitochondria) pathways controlling the cellular fate of APP processing towards the amyloidogenic route subserve the local, antibody-mediated anti-amyloidogenic action in vivo. Our results show for the first time that similar molecular and metabolic retino-cerebral pathways are modulated in coordinated fashion in response to 12A12mAb treatment to tackle the neurosensorial Aβ accumulation in AD neurodegeneration.
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2018-01-25 | PXD006214 | Pride
Project description:Amyloid beta (Aβ) monomers aggregate to form fibrils and amyloid plaques, which is one of the important mechanisms in the pathogenesis of Alzheimer's disease (AD). Since the Aβ1-42 aggregation has prominent role in plaque formation, which eventually lead to the patient's brain lesions and cognitive impairment, an increasing number of studies have been devoted to reduce Aβ aggregation process to slow down AD progression. Since the diphenylalanine (FF) sequence is critical for amyloid aggregation, and it has been shown that magnetic fields can affect the alignment of peptide assembly due to the diamagnetic anisotropy of aromatic rings, here we used a moderate-intensity rotating magnetic field (RMF) to explore its effect on Aβ aggregation and AD pathogenesis. Our data showed that RMF can directly inhibit Aβ amyloid fibril formation and reduce Aβ-induced cytotoxicity on neural cells in vitro. Using the AD mouse model APP/PS1, we found that the RMF can restore their motor ability to the healthy control level. Their cognitive impairments, including exploration ability, spatial and non-spatial memory abilities, were also significantly alleviated. Tissue examinations reveal that RMF has reduced amyloid plaque accumulation, attenuated microglial activation ,and reduced oxidative stress in the APP/PS1 mouse brain. Therefore, our data demonstrate the great potential of RMF to be developed as a non-invasive, high-penetration physical approach to be applied in the treatment of AD.
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Project description:Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia, characterized by deposition of extracellular amyloid-beta (Aβ) aggregates and intraneuronal hyperphosphorylated Tau. Many AD risk genes, identified in genome-wide association studies (GWAS), are expressed in microglia, the innate immune cells of the central nervous system. Specific subtypes of microglia emerged in relation to AD pathology, such as disease-associated microglia (DAMs), which increased in number with age in amyloid mouse models and in human AD cases. However, the initial transcriptional changes in these microglia in response to amyloid are still unknown. Here, to determine early changes in microglia gene expression, hippocampal microglia from APPswe/PS1dE9 (APP/PS1) mice and wildtype littermates were isolated and analyzed by RNA sequencing (RNA-seq). By bulk RNA-seq, transcriptomic changes were detected in hippocampal microglia from 6-months-old APP/PS1 mice. By performing single cell RNA-seq of CD11c-positive and negative microglia from 6-months-old APP/PS1 mice and analysis of the transcriptional trajectory from homeostatic to CD11c-positive microglia, we identified a set of genes that potentally reflect the initial response of microglia to Aβ.
2024-04-01 | GSE226938 | GEO
Project description:Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia, characterized by deposition of extracellular amyloid-beta (Aβ) aggregates and intraneuronal hyperphosphorylated Tau. Many AD risk genes, identified in genome-wide association studies (GWAS), are expressed in microglia, the innate immune cells of the central nervous system. Specific subtypes of microglia emerged in relation to AD pathology, such as disease-associated microglia (DAMs), which increased in number with age in amyloid mouse models and in human AD cases. However, the initial transcriptional changes in these microglia in response to amyloid are still unknown. Here, to determine early changes in microglia gene expression, hippocampal microglia from APPswe/PS1dE9 (APP/PS1) mice and wildtype littermates were isolated and analyzed by RNA sequencing (RNA-seq). By bulk RNA-seq, transcriptomic changes were detected in hippocampal microglia from 6-months-old APP/PS1 mice. By performing single cell RNA-seq of CD11c-positive and negative microglia from 6-months-old APP/PS1 mice and analysis of the transcriptional trajectory from homeostatic to CD11c-positive microglia, we identified a set of genes that potentally reflect the initial response of microglia to Aβ.
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2014-08-12 | E-GEOD-31372 | biostudies-arrayexpress