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Astrocytic Nrf2 reduces phospho-tau accumulation and neurodegeneration A Schematic illustrating the crossing of MAPTP301S and GFAP-Nrf2 mice. B, C NeuN staining of upper cortical layers of mice at early-stage disease. Mean ± SEM shown. F (2, 21) = 28.83, p = 9.5E−7 (1-way ANOVA); * Post-hoc (Bonferroni) p values: 3.8E−07, 0.0028. N = 6 WT, 9 MAPTP301S and 9 MAPTP301S_X_GFAP-Nrf2 mice. Example pictures shown in (C); scale bar 20 µm. D, E Cortical slices were subject to AT8 immunofluorescent staining, and positive cells counted. Mean ± SEM shown from n = 10 MAPTP301S and n = 7 MAPTP301S_X_GFAP-Nrf2 mice. Where more than one slice was analysed per mouse, and average was taken to provide a single data point per mouse. Main genotype effect: F (1, 60) = 26.54, p = 3.02E−6 (two-way ANOVA). Post-hoc (Bonferroni) p values: 0.010, 0.0017. D Shows example pictures, scale bar 100 µm.
Source publication
Alzheimer’s disease (AD) alters astrocytes, but the effect of Aß and Tau pathology is poorly understood. TRAP-seq translatome analysis of astrocytes in APP/PS1 ß-amyloidopathy and MAPT P301S tauopathy mice revealed that only Aß influenced expression of AD risk genes, but both pathologies precociously induced age-dependent changes, and had distinct...
Citations
... Astrocytes are a diverse type of glial cells with remarkable plasticity that play a crucial role in maintaining the overall health and function of the central nervous system (CNS) (Allen and Eroglu, 2017;Ben Haim and Rowitch, 2017). In AD, astrocytes respond both functionally and morphologically to the neuropathologic markers of the disease, such as the clearance of excess neurotransmitters and toxic beta amyloid (Aβ) and tau protein forms of toxins (Jiwaji et al., 2022). Asterocyte dysfunction significantly influences the severity and developmental trajectory of AD (Tcw et al., 2022). ...
... Early studies designed to characterize reactive astrocytes using bulk transcriptomic analyses described two states induced by acute traumatic insults in models of ischemic stroke and endotoxemia 1 . However, more recent single-cell RNA sequencing studies in mouse models of chronic neurodegeneration have revealed complex gene expression profiles within the broad population of reactive astrocytes 9,[13][14][15][16][17][18] . Although these recent analyses highlighted transcriptional profiles of reactive astrocytes, a more detailed description of the heterogeneity of reactive astrocytes across chronic neurodegenerative diseases, including Alzheimer's Disease (AD) and Multiple Sclerosis (MS), is lacking. ...
Astrocytes play a pivotal role in central nervous system homeostasis and neuroinflammation. Despite advancements in single-cell analyses, the heterogeneity of reactive astrocytes in neurodegenerative diseases, particularly across species, remains understudied. Here, we present an integrated atlas of 187,000 astrocytes from mouse models of Alzheimer's (AD) and multiple sclerosis (MS) alongside 438,000 astrocytes from AD, MS, and Parkinson's (PD) patients. Our analysis identified four distinct mouse astrocyte clusters, including two disease-associated astrocyte (DAA) clusters, DAA1 and DAA2. DAA1 displayed reactivity resembling responses to acute stimuli, including endotoxemia, while DAA2 expressed well-known AD risk genes. In an AD model, DAA1 and DAA2 exhibited distinct spatial relationships to amyloid plaques. In humans, we identified eight distinct astrocyte clusters, encompassing homeostatic and disease-associated subtypes. Cross-species analysis linked disease-associated clusters while also highlighting divergent expression in others. Our astrocyte atlas is available through a user-friendly, searchable website: http://research-pub.gene.com/AstroAtlas/.
... Of note, the area labelled for the constitutively expressed astrocyte marker ALDH1L1 was not significantly different between CTE lesion and non-lesion areas suggesting no change in astrocyte density. Given the neuroinflammatory role of GFAP [36][37][38][39], CHI3L1 [40][41][42] and NQO1 [43][44][45][46], their increased coverage around the lesion vessels is an indication of a vessel-associated, astrocyte inflammatory profile in CTE. To date, there have been very few studies characterising astrocyte reactivity in CTE. ...
Chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive head injuries, is characterised by perivascular hyperphosphorylated tau (p-tau) accumulations within the depths of cortical sulci. Although the majority of CTE literature focuses on p-tau pathology, other pathological features such as glial reactivity, vascular damage, and axonal damage are relatively unexplored. In this study, we aimed to characterise these other pathological features, specifically in CTE p-tau lesion areas, to better understand the microenvironment surrounding the lesion. We utilised multiplex immunohistochemistry to investigate the distribution of 32 different markers of cytoarchitecture and pathology that are relevant to both traumatic brain injury and neurodegeneration. We qualitatively assessed the multiplex images and measured the percentage area of labelling for each marker in the lesion and non-lesion areas of CTE cases. We identified perivascular glial reactivity as a prominent feature of CTE p-tau lesions, largely driven by increases in astrocyte reactivity compared to non-lesion areas. Furthermore, we identified astrocytes labelled for both NAD(P)H quinone dehydrogenase 1 (NQO1) and L-ferritin, indicating that lesion-associated glial reactivity may be a compensatory response to iron-induced oxidative stress. Our findings demonstrate that perivascular inflammation is a consistent feature of the CTE pathognomonic lesion and may contribute to the pathogenesis of brain injury-related neurodegeneration.
... These findings bolster the evidence that circadian clock proteins are involved in neurodegenerative diseases by implicating BMAL1 in the regulation of proteostasis within astrocytes. The potential for downstream genes of Bmal1 to temporally regulate proteostasis presents new therapeutic opportunities for targeting these processes in the context of the disease [104]. ...
... Some signals may be harmful, while others may be protective. Recent studies have started to reveal the variety of astrocyte activation phenotypes that extend apart from GFAP, with unique gene expressions associated with effects ranging from neurotoxic to neurotrophic [32,43,54,104]. ...
... Profiling astrocyte responses to tau and Aβ pathology has uncovered that their "reactive" state exhibits signatures indicative of cellular dysfunction and inflammation alongside adaptive protective responses. If these adaptive responses can be effectively harnessed, they may slow the aggregation of tau and α-synuclein and mitigate the progression of both diseases [104]. Transcriptomic profiling studies of astrocytes in neurodegenerative conditions indicate multiple modes of astrocyte activation, which vary depending on the disease state and may involve differential expression of GFAP [104,[107][108][109][110]. This complexity suggests that astrocyte reactivity cannot be accurately captured by a simple binary classification system [44]. ...
Astrocyte activation is a critical aspect of brain health and disease, and the central circadian clock protein BMAL1 has emerged as a regulator of astrogliosis and inflammatory gene expression. Bmal1 deletion in astrocytes reprograms endolysosomal transcriptional pathways, inducing endocytosis, lysosomal degradation, and autophagic activity. This regulation of proteostasis by BMAL1 implicates circadian clock proteins in neurodegenerative diseases. Studies suggest that astrocyte activation is a complex process with diverse phenotypes beyond classic markers such as GFAP, exhibiting neurotoxic and neuroprotective effects. Deletion of Bmal1 in astrocytes has shown protective effects in models of Alzheimer’s disease (AD) and Parkinson’s disease (PD), influencing Aβ accumulation and α-syn pathology, respectively, through a state of protective astrocyte activation that mitigates tauopathy and α-syn pathology, possibly through the induction of the chaperone protein BAG3. These findings suggest that BMAL1 is crucial in regulating astrocytic function and neuroprotection in neurodegenerative diseases. This review explores the relationship between circadian dysfunction and the development/progression of AD and PD. Furthermore, it recapitulates the most recent findings on manipulating the clock protein BMAL1 and its potential protective effects in astrocytes.
... A research group conducted a detailed analysis of gene alteration in astrocytes within APP/PS1 β-amyloidopathy and MAPT P301S tauopathy mouse models [141]. The Nrf2 gene was found to be significantly enriched in astrocytes in both Aβ and TAU pathology models. ...
... Additionally, astrocytic NRF2 reduced both the number and area of Aβ plaque in Aβ pathology mice. In both AD mouse models, NRF2 overexpression not only alleviated transcriptional disruptions but also rescued cognitive deficits, underscoring its therapeutic potential [141]. To conclude, the influence of astrocytic NRF2 may help prevent AD progression and preserve brain function. ...
Alzheimer’s disease (AD) is a polygenic, multifactorial neurodegenerative disorder and remains the most prevalent form of dementia, globally. Despite decades of research efforts, there is still no effective cure for this debilitating condition. AD research has increasingly focused on transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) as a potential therapeutic target. NRF2 plays a crucial role in protecting cells and tissues from environmental stressors, such as electrophiles and reactive oxygen species. Recently, an increasing number of studies have demonstrated that NRF2 is a key regulator in AD pathology. NRF2 is highly expressed in microglia, resident macrophages in the central nervous system, and contributes to neuroinflammation, phagocytosis and neurodegeneration in AD. NRF2 has been reported to modulate microglia-induced inflammation and facilitate the transition from homeostatic microglia to a disease-associated microglia subset. Genetic and pharmacological activation of NRF2 has been demonstrated to improve cognitive function. Here, we review the current understanding of the involvement of NRF2 in AD and the critical role that NRF2 plays in microglia in the context of AD. Our aim is to highlight the potential of targeting NRF2 in the microglia as a promising therapeutic strategy for mitigating the progression of AD.
... 45 GFAP is a marker of astrocyte reactivity, and reactive astrocytes can exacerbate or suppress neuropathology. 46 Astrocytes are activated or recruited to the site of injury or pathology to assist with Aβ clearance and degradation and help maintain homeostasis when the disease is developing. 47 ...
... ,48 That is, their function and response to protein misfolding and aggregation are considered neuroprotective or healthy at first before becoming pro-inflammatory.[46][47][48] One hypothesis is that, because mutation carriers were 15 years on average from MCI onset and at an age when they are accumulating amyloid plaques,4 higher levels of GFAP may represent an astrocytic response to the accumulation of amyloid that could be the immune system's attempt to maintain homeostasis.However, this is purely speculative, and more research is needed to understand this relationship, including studies with larger samples that can replicate the findings.Our study had several shortcomings. ...
Objective
Physical activity (PA) has been linked to reduced Alzheimer's disease (AD) risk. However, less is known about its effects in the AD preclinical stage. We aimed to investigate whether greater PA was associated with lower plasma biomarkers of AD pathology, neural injury, reactive astrocytes, and better cognition in individuals with autosomal‐dominant AD due to the presenilin‐1 E280A mutation who are virtually guaranteed to develop dementia.
Methods
Twenty‐eight cognitively unimpaired mutation carriers (ages x̄ = 29.28) wore a FitBit Charge‐4 for 14 days. We calculated their average steps to measure locomotion, and Training Impulse (TRIMP) to quantify the intensity and duration of PAs using heart rate. Plasma amyloid beta 42/40 ratio, phosphorylated tau 181, neurofilament light chain, and glial fibrillary acidic protein (GFAP) were measured. Cognition was assessed with the Consortium to Establish a Registry for Alzheimer's Disease word list learning and delayed recall, Trail Making Test Part A, and Wechsler Adult Intelligence Scale‐version IV Digit Span Backward. We conducted multiple linear regressions controlling for age, sex, body mass index, and education.
Results
There were no associations among steps or TRIMP with plasma biomarkers or cognition. Greater TRIMP was related to higher GFAP levels.
Conclusions
PA was not associated with cognition or plasma biomarkers. However, greater intensity and duration of PAs were related to higher GFAP. Participants engaged very little in moderate to vigorous PA. Therefore, light PA may not exert a significant protective effect in preclinical AD. Future work with larger samples and longitudinal data is needed to elucidate further the potential impact of PA on AD progression in the preclinical stages.
Highlights
Locomotion (average steps) was not associated with plasma biomarkers or cognition.
Greater training load (training impulse) was related to higher glial fibrillary acidic protein levels in mutation carriers.
Light physical activity may not suffice to exert a protective effect on Alzheimer's disease.
... Astrocytes are critical for maintaining brain homeostasis 2 , and the emerging view from experimental data is that reactive astrogliosis may contribute to neurodegeneration through both gains of toxic functions and loss of normal functions 1 . Indeed, numerous astrocyte-specific transcriptomic studies in various transgenic mouse models of AD [3][4][5][6][7][8] have supported this view. Recent single-nucleus RNA-sequencing (snRNA-seq) studies [9][10][11][12][13][14][15][16][17] have begun to unravel the molecular underpinnings of reactive astrocytes in the human AD brain as well, but several questions remain-(1) are there regional differences in astrocyte gene expression in the normal aging brain? ...
... Donor-level expression of representative genes for each spatial trajectory is shown in Supplementary Fig. 4b. Previous transcriptomic studies comparing AD mouse models have reported similarities and differences in astrocyte responses to Aβ plaques versus pTau NFTs 5,7,33 . To test whether the spatial trajectories of astrocyte gene expression are also related to local Aβ and pTau levels, we correlated the average standardized expression of each of these spatial gene sets for each brain region and donor with the Aβ plaque burden and the pTau/tau ratio measured in the same brain regions and donors, while controlling for within-donor correlation ( Fig. 3b and Supplementary Fig. 4c). ...
... On the other hand, genes correlated with both Aβ and pTau levels (a.k.a. pan-reactive) consisted of an upregulation of GPCR-mediated signaling and intracellular trafficking and a downregulation of energy metabolism, further suggesting a synergistic effect of Aβ and pTau on the astrocyte transcriptome 5 . The latter result also suggests that astrocytes undergo an energy failure as a result of chronic exposure to both Aβ and pTau. ...
Astrocytes are crucial to brain homeostasis, yet their changes along the spatiotemporal progression of Alzheimer’s disease (AD) neuropathology remain unexplored. Here we performed single-nucleus RNA sequencing of 628,943 astrocytes from five brain regions representing the stereotypical progression of AD pathology across 32 donors spanning the entire normal aging to severe AD continuum. We mapped out several unique astrocyte subclusters that exhibited varying responses to neuropathology across the AD-vulnerable neural network (spatial axis) or AD pathology stage (temporal axis). The proportion of homeostatic, intermediate and reactive astrocytes changed only along the spatial axis, whereas two other subclusters changed along the temporal axis. One of these, a trophic factor-rich subcluster, declined along pathology stages, whereas the other increased in the late stage but returned to baseline levels in the end stage, suggesting an exhausted response with chronic exposure to neuropathology. Our study underscores the complex dynamics of astrocytic responses in AD.
... In pathological conditions, they mediate inflammatory responses to amyloid plaques, tau tangles, and other stimuli [8,9]. While initially protective, chronic activation of these systems leads to the release of pro-inflammatory cytokines, disrupting normal functions and exacerbating neuronal injury [10,11]. Recent studies have shown that neuroinflammation is present from the earliest stages of AD, often preceding cognitive decline and overlapping with Aβ deposition [12]. ...
The identification of neuroinflammation as a critical factor in Alzheimer’s disease (AD) has expanded the focus of research beyond amyloid-β and tau pathology. The neuroinflammatory fluid biomarkers GFAP, sTREM2, and YKL-40 have gained attention for their potential in early detection and monitoring of disease progression. Plasma GFAP has demonstrated promise in predicting the conversion from mild cognitive impairment to AD dementia, while sTREM2 highlights microglial activation, although there are conflicting results regarding its dynamics in AD pathogenesis. Advanced imaging techniques, such as PET tracers targeting TSPO and MAO-B, have also been developed to visualize glial activation in vivo, offering spatial and temporal insights into neuroinflammatory processes. However, the clinical implementation of these biomarkers faces challenges due to their lack of specificity, as many of them can be elevated in other conditions. Therapeutic strategies targeting neuroinflammation are emerging, with TREM2-targeting therapies and antidiabetic drugs like GLP-1 receptor agonists showing potential in modulating microglial activity. Nevertheless, the complexity of neuroinflammation, which encompasses both protective and harmful responses, necessitates further research to fully unravel its role and optimize therapeutic approaches for AD.
... A Random Forest classifier that predicts AD versus Control was trained on the averaged PAC scores (Fig. 2d) and its SHAP values were utilized to prioritize cell subclasses important for AD (Fig. 2e, Supplementary Data 1). Among these, microglia were ranked the highest, followed by astrocytes, both of which have previously been associated with AD [22][23][24] . Although oligodendrocytes appear as the most prominent cell subclass with the greatest number of cells (Extended Fig. 2a), they were ranked relatively low, suggesting the PAC based cell type prioritization is not influenced by cell abundance 25 , unlike existing methods that utilize the number of differentially expressed genes 25,26 . ...
The complexity of Alzheimer's disease (AD) manifests in diverse clinical phenotypes, including cognitive impairment and neuropsychiatric symptoms (NPSs). However, the etiology of these phenotypes remains elusive. To address this, the PsychAD project generated a population-level single-nucleus RNA-seq dataset comprising over 6 million nuclei from the prefrontal cortex of 1,494 individual brains, covering a variety of AD-related phenotypes that capture cognitive impairment, severity of pathological lesions, and the presence of NPSs. Leveraging this dataset, we developed a deep learning framework, called Phenotype Associated Single Cell encoder (PASCode), to score single-cell phenotype associations, and identified ~1.5 million phenotype associate cells (PACs). We compared PACs within 27 distinct brain cell subclasses and prioritized cell subpopulations and their expressed genes across various AD phenotypes, including the upregulation of a reactive astrocyte subtype with neuroprotective function in AD resilient donors. Additionally, we identified PACs that link multiple phenotypes, including a subpopulation of protoplasmic astrocytes that alter their gene expression and regulation in AD donors with depression. Uncovering the cellular and molecular mechanisms underlying diverse AD phenotypes has the potential to provide valuable insights towards the identification of novel diagnostic markers and therapeutic targets. All identified PACs, along with cell type and gene expression information, are summarized into an AD-phenotypic single-cell atlas for the research community.
... Aβ and Tau can be engulfed by supporting cells of the neuronal microenvironment including astrocytes and microglia, which may alleviate the proteinaceous burden by degradation of Aβ and Tau aggregates but also induce neuroinflammation and increase pathology spreading [148,149]. Whether astrocytes and microglia are promoters or rescuers of pathology spreading in AD remains debatable. Nevertheless, there is growing evidence that microglial and astrocytic surveillance of the neuronal environment effectively promotes the degradation of extracellular Aβ and Tau aggregates, limiting their propagation by preventing neuronal uptake [150][151][152]. ...
Alzheimer’s disease (AD) is the most common type of dementia worldwide. The etiopathogenesis of this disease remains unknown. Currently, several hypotheses attempt to explain its cause, with the most well-studied being the cholinergic, beta-amyloid (Aβ), and Tau hypotheses. Lately, there has been increasing interest in the role of immunological factors and other proteins such as alpha-synuclein (α-syn) and transactive response DNA-binding protein of 43 kDa (TDP-43). Recent studies emphasize the role of tunneling nanotubes (TNTs) in the spread of pathological proteins within the brains of AD patients. TNTs are small membrane protrusions composed of F-actin that connect non-adjacent cells. Conditions such as pathogen infections, oxidative stress, inflammation, and misfolded protein accumulation lead to the formation of TNTs. These structures have been shown to transport pathological proteins such as Aβ, Tau, α-syn, and TDP-43 between central nervous system (CNS) cells, as confirmed by in vitro studies. Besides their role in spreading pathology, TNTs may also have protective functions. Neurons burdened with α-syn can transfer protein aggregates to glial cells and receive healthy mitochondria, thereby reducing cellular stress associated with α-syn accumulation. Current AD treatments focus on alleviating symptoms, and clinical trials with Aβ-lowering drugs have proven ineffective. Therefore, intensifying research on TNTs could bring scientists closer to a better understanding of AD and the development of effective therapies.
