Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer’s disease

Zalocusky, Kelly A.; Najm, Ramsey; Taubes, Alice; Hao, Yanxia; Yoon, Seo Yeon; Koutsodendris, Nicole; Nelson, Maxine; Rao, Antara T.; Bennett, David A.; Bant, Jason S.; Amornkul, Dah-Eun J; Xu, Qin; An, Alice; Cisne-Thomson, Olga; Huang, Yadong

doi:10.1038/s41593-021-00851-3

Cited by 117 publications

(126 citation statements)

References 61 publications

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“…Consistent with signatures of intercellular proteostatic stress, we observed that NFT-upregulated genes involve actin cytoskeleton and endocytosis primarily in CA1 and ECL2/3 neurons, and ubiquitin mediated proteolysis more broadly. In addition, we detected recurrent upregulation of several viral-related pathways, suggesting an inflammatory neuronal component consistent with recent findings in mouse models and human cortical AD samples 40 . Unlike EC neuron types, NFT-responsive genes in CA1 neurons involve the upregulation of KEEG neurodegenerative disease pathways, including AD, Hungtington’s, and Parkinson’s disease; along with increased insulin and chemokine signaling, and the specific downregulation of glutamatergic synaptic and calcium signaling genes.…”

Section: Resultssupporting

confidence: 90%

Single-cell anatomical analysis of human hippocampus and entorhinal cortex uncovers early-stage molecular pathology in Alzheimer’s disease

Dávila-Velderrain

Mathys

Mohammadi

et al. 2021

Preprint

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The human hippocampal formation plays a central role in Alzheimer’s disease (AD) progression, cognitive traits, and the onset of dementia; yet its molecular states in AD remain uncharacterized. Here, we report a comprehensive single-cell transcriptomic dissection of the human hippocampus and entorhinal cortex across 489,558 cells from 65 individuals with varying stages of AD pathology. We transcriptionally characterize major brain cell types and neuronal classes, including 17 glutamatergic and 8 GABAergic neuron subpopulations. Combining evidence from human and mouse tissue-microdissection, neuronal cell isolation and spatial transcriptomics, we show that single-cell expression patterns capture fine-resolution neuronal anatomical topography. By stratifying subjects into early and late pathology groups, we uncover stage-dependent and cell-type specific transcriptional modules altered during AD progression. These include early-stage cell-type specific dysregulation of cellular and cholesterol metabolism, late-stage neuron-glia alterations in neurotransmission, and late-stage signatures of cellular stress, apoptosis, and DNA damage broadly shared across cell types. Late-stage signatures show signs of convergence in hippocampal and cortical cells, while early changes diverge; highlighting the relevance of characterizing molecular pathology across brain regions and AD progression. Finally, we characterize neuron subregion-specific responses to AD pathology and show that CA1 pyramidal neurons are the most transcriptionally altered while CA3 and dentate gyrus granule neurons the least. Our study provides a valuable resource to extend cell type-specific studies of AD to clinically relevant brain regions affected early by pathology in disease progression.

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Section: Resultssupporting

confidence: 90%

Single-cell anatomical analysis of human hippocampus and entorhinal cortex uncovers early-stage molecular pathology in Alzheimer’s disease

Dávila-Velderrain

Mathys

Mohammadi

et al. 2021

Preprint

Self Cite

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“…Cytotoxic T cells are cells that recognise antigens presented usually due to viral infections, and were recently reported to invade the CNS during inflammation caused by COVID-19 [ 74 ]. Some vulnerable neurons were also reported to increase antigen-presenting MHC-I on their surface and this was related to exacerbation of tau pathology [ 75 ]. While perforin/granzyme B in tauopathies has not been reported, we thought it is important to include this mechanism of cell death in Table 1 , especially if secondary infections occur that escape treatment.…”

Section: Tau Aggregation or Pathology And Non-cell Autonomous Death Mechanismsmentioning

confidence: 99%

Tau aggregation and its relation to selected forms of neuronal cell death

Tolkovsky

Spillantini

2021

Essays in Biochemistry

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How neurons die in neurodegenerative diseases is still unknown. The distinction between apoptosis as a genetically controlled mechanism, and necrosis, which was viewed as an unregulated process, has blurred with the ever-increasing number of necrotic-like death subroutines underpinned by genetically defined pathways. It is therefore pertinent to ask whether any of them apply to neuronal cell death in tauopathies. Although Alzheimer’s disease (AD) is the most prevalent tauopathy, tauopathies comprise an array of over 30 diseases in which the cytoplasmic protein tau aggregates in neurons, and also, in some diseases, in glia. Animal models have sought to distil the contribution of tau aggregation to the cell death process but despite intensive research, no one mechanism of cell death has been unequivocally defined. The process of tau aggregation, and the fibrillar structures that form, touch on so many cellular functions that there is unlikely to be a simple linear pathway of death; as one is blocked another is likely to take the lead. It is timely to ask how far we have advanced into defining whether any of the molecular players in the new death subroutines participate in the death process. Here we briefly review the currently known cell death routines and explore what is known about their participation in tau aggregation-related cell death. We highlight the involvement of cell autonomous and the more recent non-cell autonomous pathways that may enhance tau-aggregate toxicity, and discuss recent findings that implicate microglial phagocytosis of live neurons with tau aggregates as a mechanism of death.

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“…These results suggest selective vulnerability depending on AD pathogenesis and pathologies. As efforts have been made to comprehensively characterise molecular mechanisms of such selective vulnerability in both humans and mouse models [149][150][151][152][153], deficits at the neural circuit level will also become clear in coming years.…”

Section: Gamma Oscillations and Ad In Mouse Modelsmentioning

confidence: 99%

Mutual Interactions between Brain States and Alzheimer’s Disease Pathology: A Focus on Gamma and Slow Oscillations

Byron

Семенова

Sakata

2021

Biology

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Brain state varies from moment to moment. While brain state can be defined by ongoing neuronal population activity, such as neuronal oscillations, this is tightly coupled with certain behavioural or vigilant states. In recent decades, abnormalities in brain state have been recognised as biomarkers of various brain diseases and disorders. Intriguingly, accumulating evidence also demonstrates mutual interactions between brain states and disease pathologies: while abnormalities in brain state arise during disease progression, manipulations of brain state can modify disease pathology, suggesting a therapeutic potential. In this review, by focusing on Alzheimer’s disease (AD), the most common form of dementia, we provide an overview of how brain states change in AD patients and mouse models, and how controlling brain states can modify AD pathology. Specifically, we summarise the relationship between AD and changes in gamma and slow oscillations. As pathological changes in these oscillations correlate with AD pathology, manipulations of either gamma or slow oscillations can modify AD pathology in mouse models. We argue that neuromodulation approaches to target brain states are a promising non-pharmacological intervention for neurodegenerative diseases.

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Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer’s disease

Cited by 117 publications

References 61 publications

Single-cell anatomical analysis of human hippocampus and entorhinal cortex uncovers early-stage molecular pathology in Alzheimer’s disease

Single-cell anatomical analysis of human hippocampus and entorhinal cortex uncovers early-stage molecular pathology in Alzheimer’s disease

Tau aggregation and its relation to selected forms of neuronal cell death

Mutual Interactions between Brain States and Alzheimer’s Disease Pathology: A Focus on Gamma and Slow Oscillations

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