Distinct transcriptomic responses to Ab plaques, neurofibrillary tangles, and APOE in Alzheimer’s disease
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ABSTRACT:
PROVIDER: PRJNA942219 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24019200_1.fastq.gz | Fastqsanger.gz | |||
| SRR24019200_2.fastq.gz | Fastqsanger.gz | |||
| SRR24019201_1.fastq.gz | Fastqsanger.gz | |||
| SRR24019201_2.fastq.gz | Fastqsanger.gz | |||
| SRR24019202_1.fastq.gz | Fastqsanger.gz |
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Project description:INTRODUCTION: Omics studies have revealed that various brain cell types undergo profound molecular changes in Alzheimer’s disease (AD) but the spatial relationships with plaques and tangles and APOE-linked differences remain unclear. METHODS: We performed laser capture microdissection of Ab plaques, the 50mm halo around them, tangles with the 50mm halo around them, and areas distant (>50mm) from plaques and tangles in the temporal cortex of AD and control donors, followed by RNA-sequencing. RESULTS: Ab plaques exhibited upregulated microglial (neuroinflammation) and downregulated neuronal (neurotransmission/energy metabolism) genes, whereas tangles had mostly downregulated neuronal genes. Ab plaques had more differentially expressed genes than tangles. We identified a gradient Ab plaque>peri-plaque>tangle>distant for these changes. AD APOEe4 homozygotes had greater changes than APOEe3 across locations, especially within Ab plaques. DISCUSSION: Transcriptomic changes in AD consist primarily of neuroinflammation and neuronal dysfunction, are spatially associated mainly with Ab plaques, and are exacerbated by the APOEe4 allele.
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Project description:Alzheimer’s disease (AD) is a complex neurodegenerative disorder that develops over decades. AD brain proteomics reveals vast alterations in protein levels and numerous altered biologic pathways. Here, we compare AD brain proteome and network changes with the brain proteomes of amyloid b (Ab)-depositing mice to identify conserved and divergent protein networks with the conserved networks identifying an Ab amyloid responsome. Proteins in the most conserved network (M42) accumulate in plaques, cerebrovascular amyloid (CAA), and/or dystrophic neuronal processes, and overexpression of two M42 proteins, midkine (Mdk) and pleiotrophin (PTN), increases the accumulation of Ab in plaques and CAA. M42 proteins bind amyloid fibrils in vitro, and MDK and PTN co-accumulate with cardiac transthyretin amyloid. M42 proteins appear intimately linked to amyloid deposition and can regulate amyloid deposition, suggesting that they are pathology modifiers and thus putative therapeutic targets. We posit that amyloid-scaffolded accumulation of numerous M42+ proteins is a central mechanism mediating downstream pathophysiology in AD.
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Project description:One of the hallmarks of Alzheimer’s disease is the presence of extracellular diffuse and fibrillar plaques predominantly consisting of the amyloid-β (Aβ) peptide. ApoE influences the deposition of amyloid pathology through affecting the clearance and aggregation of monomeric Aβ in the brain. In addition to influencing Aβ metabolism, increasing evidence suggests that apoE influences microglial function in neurodegenerative diseases. Here, we characterize the impact that apoE has on amyloid pathology and the innate immune response in APPPS1∆E9 and APPPS1-21 transgenic mice. We report that Apoe deficiency reduced fibrillar plaque deposition consistent with previous studies. However, fibrillar plaques in Apoe-deficient mice exhibited a striking reduction in plaque compaction. Hyperspectral fluorescent imaging using luminescent conjugated oligothiophenes identified distinct Aβ morphotypes in Apoe-deficient mice. We also observed a significant reduction in fibrillar plaque-associated microgliosis and activated microglial gene expression in Apoe-deficient mice, along with significant increases in dystrophic neurites around fibrillar plaques. Our results suggest that apoE is critical in stimulating the innate immune response to amyloid pathology.
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Project description:Amyloid plaque heterogeneity is a hallmark of Alzheimer's disease (AD), yet the mechanisms governing plaque diversity and its relationship to disease progression remain poorly understood. Although both diffuse and neuritic plaques are present in AD brain tissue, we do not know how these distinct conformations arise or influence pathological outcomes. Here, we developed transgenic mouse models expressing identical APP constructs in either glutamatergic or GABAergic neurons to investigate how cellular context shapes amyloid pathology. This approach revealed that the cellular source of APP influences both the biochemical composition and structural characteristics of resulting Aβ deposits. APP expressed in GABAergic neurons generated exclusively diffuse plaques with elevated Aβ42/Aβ40 ratios that failed to induce gliosis, while glutamatergic expression produced primarily neuritic plaques surrounded by activated microglia. Differences in deposit characteristics appeared to arise from fundamental variations in APP processing between excitatory and inhibitory neurons. Moreover, only neuritic plaques generated by glutamatergic neurons caused behavioral deficits, while diffuse plaques from GABAergic neurons did not impair cognition despite substantial amyloid burden. These findings may provide new insight into the mechanisms underlying amyloid heterogeneity in AD and suggest that plaque conformation, rather than simply amyloid load, may influence cognitive trajectories. snRNA-seq revealed that microglia from the excitatory models showed many DAM genes were upregulated, which were absent in the inhibitory model. The data also revealed there were no changes in expression of key APP processing enzymes between excitatory or inhibitory neurons in each model.
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Project description:Microglia play a pivotal role in the maintenance of brain homeostasis, but lose their homeostatic function during the course of neurodegenerative disorders. We identified a specific APOE-dependent molecular signature in microglia isolated from mouse models of amyotrophic lateral sclerosis, multiple sclerosis and Alzheimer’s disease (SOD1, EAE and APP-PS1) and in microglia surrounding neuritic A-plaques in human Alzheimer’s disease brain. This is mediated by a switch from a (M0)-homeostatic to (MGnD)-neurodegenerative phenotype following phagocytosis of apoptotic neurons via the TREM2-APOE pathway. TREM2 induces APOE signaling which is a negative regulator of the transcription program in M0-homeostatic microglia. Targeting the TREM2-APOE pathway restores the M0-homeostatic signature of microglia in APP-PS1 and SOD1 mice and prevents from neuronal loss in an acute model of neurodegeneration. In SOD1 mice, TREM2 regulates MGnD in a gender-dependent manner. APOE-mediated MGnD microglia lose their tolerogenic function. Taken together, our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target to restore homeostatic microglia.
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Project description:Microglia play a pivotal role in the maintenance of brain homeostasis, but lose their homeostatic function during the course of neurodegenerative disorders. We identified a specific APOE-dependent molecular signature in microglia isolated from mouse models of amyotrophic lateral sclerosis, multiple sclerosis and Alzheimer’s disease (SOD1, EAE and APP-PS1) and in microglia surrounding neuritic A-plaques in human Alzheimer’s disease brain. This is mediated by a switch from a (M0)-homeostatic to (MGnD)-neurodegenerative phenotype following phagocytosis of apoptotic neurons via the TREM2-APOE pathway. TREM2 induces APOE signaling which is a negative regulator of the transcription program in M0-homeostatic microglia. Targeting the TREM2-APOE pathway restores the M0-homeostatic signature of microglia in APP-PS1 and SOD1 mice and prevents from neuronal loss in an acute model of neurodegeneration. In SOD1 mice, TREM2 regulates MGnD in a gender-dependent manner. APOE-mediated MGnD microglia lose their tolerogenic function. Taken together, our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target to restore homeostatic microglia.
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