Physiological and Pathological Ageing of Astrocytes in the Human Brain

Verkerke, Marloes; Hol, Elly M.; Middeldorp, Jinte

doi:10.1007/s11064-021-03256-7

Cited by 34 publications

(31 citation statements)

References 156 publications

(255 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The increase found by the authors is mostly due to a 58% increase in non-neuronal cells ( Han et al, 1989 ). In fact, senescence effects glia as well as neurons, with astrocytes and microglia showing hypertrophic and hyperactivated states with aging both in animals ( Duncombe et al, 2017 ; Ashraf et al, 2019 ) and humans ( Verkerke et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

The Aged Striatum: Evidence of Molecular and Structural Changes Using a Longitudinal Multimodal Approach in Mice

Giacobbo

Özalay

Mediavilla

et al. 2022

Front. Aging Neurosci.

View full text Add to dashboard Cite

To study the aging human brain requires significant resources and time. Thus, mice models of aging can provide insight into changes in brain biological functions at a fraction of the time when compared to humans. This study aims to explore changes in dopamine D1 and D2 receptor availability and of gray matter density in striatum during aging in mice and to evaluate whether longitudinal imaging in mice may serve as a model for normal brain aging to complement cross-sectional research in humans. Mice underwent repeated structural magnetic resonance imaging (sMRI), and [11C]Raclopride and [11C]SCH23390 positron emission tomography (PET) was performed on a subset of aging mice. PET and sMRI data were analyzed by binding potential (BPND), voxel- and tensor-based morphometry (VBM and TBM, respectively). Longitudinal PET revealed a significant reduction in striatal BPND for D2 receptors over time, whereas no significant change was found for D1 receptors. sMRI indicated a significant increase in modulated gray matter density (mGMD) over time in striatum, with limited clusters showing decreased mGMD. Mouse [11C]Raclopride data is compatible with previous reports in human cross-sectional studies, suggesting that a natural loss of dopaminergic D2 receptors in striatum can be assessed in mice, reflecting estimates from humans. No changes in D1 were found, which may be attributed to altered [11C]SCH23390 kinetics in anesthetized mice, suggesting that this tracer is not yet able to replicate human findings. sMRI revealed a significant increase in mGMD. Although contrary to expectations, this increase in modulated GM density may be attributed to an age-related increase in non-neuronal cells.

show abstract

Section: Discussionmentioning

confidence: 99%

The Aged Striatum: Evidence of Molecular and Structural Changes Using a Longitudinal Multimodal Approach in Mice

Giacobbo

Özalay

Mediavilla

et al. 2022

Front. Aging Neurosci.

View full text Add to dashboard Cite

show abstract

“…In summary, our systematic review of the neuropathological literature reveals the complexity of AD-associated astrocyte reaction, which has been increasingly recognised [ 1 , 3 – 6 ]. Besides biomarker discovery, these findings could inform future astrocytecentric single-cell and single-nuclei RNA-seq studies as well as spatial transcriptomic and proteomic investigations.…”

Section: Discussionmentioning

confidence: 99%

Systematic review of human post‐mortem immunohistochemical studies and bioinformatics analyses unveil the complexity of astrocyte reaction in Alzheimer's disease

Viejo

Noori

Merrill

et al. 2021

Neuropathology Appl Neurobio

View full text Add to dashboard Cite

Aims Reactive astrocytes in Alzheimer's disease (AD) have traditionally been demonstrated by increased glial fibrillary acidic protein (GFAP) immunoreactivity; however, astrocyte reaction is a complex and heterogeneous phenomenon involving multiple astrocyte functions beyond cytoskeletal remodelling. To better understand astrocyte reaction in AD, we conducted a systematic review of astrocyte immunohistochemical studies in post‐mortem AD brains followed by bioinformatics analyses on the extracted reactive astrocyte markers. Methods NCBI PubMed, APA PsycInfo and WoS‐SCIE databases were interrogated for original English research articles with the search terms ‘Alzheimer's disease’ AND ‘astrocytes.’ Bioinformatics analyses included protein–protein interaction network analysis, pathway enrichment, and transcription factor enrichment, as well as comparison with public human ‐omics datasets. Results A total of 306 articles meeting eligibility criteria rendered 196 proteins, most of which were reported to be upregulated in AD vs control brains. Besides cytoskeletal remodelling (e.g., GFAP), bioinformatics analyses revealed a wide range of functional alterations including neuroinflammation (e.g., IL6, MAPK1/3/8 and TNF), oxidative stress and antioxidant defence (e.g., MT1A/2A, NFE2L2, NOS1/2/3, PRDX6 and SOD1/2), lipid metabolism (e.g., APOE, CLU and LRP1), proteostasis (e.g., cathepsins, CRYAB and HSPB1/2/6/8), extracellular matrix organisation (e.g., CD44, MMP1/3 and SERPINA3), and neurotransmission (e.g., CHRNA7, GABA, GLUL, GRM5, MAOB and SLC1A2), among others. CTCF and ESR1 emerged as potential transcription factors driving these changes. Comparison with published ‐omics datasets validated our results, demonstrating a significant overlap with reported transcriptomic and proteomic changes in AD brains and/or CSF. Conclusions Our systematic review of the neuropathological literature reveals the complexity of AD reactive astrogliosis. We have shared these findings as an online resource available at https://www.astrocyteatlas.org/.

show abstract

“…Despite the differential contributions of the glymphatic system and the IPAD pathway to the clearance of cerebral fluids and waste material are not completely grasped, it is accepted that astrocytes play a pivotal role in the exchange of fluids, based on studies showing that, in AQP4 KO mice, cerebrospinal fluid influx as well as CNS clearance were decreased ( Iliff et al, 2012 ; Braun and Iliff, 2020 ). Another essential function of astrocytes is glutamate uptake and release, which is very important for the maintenance of CNS homeostasis ( Dejakaisaya et al, 2021 ; van Putten et al, 2021 ; Verkerke et al, 2021 ). Astrocytes also have a critical role in the brain antioxidant system maintenance and in the production of glutathione, an important modulator of oxidative stress and aging ( Bains and Shaw, 1997 ; Venkateshappa et al, 2012 ; Howarth et al, 2017 ; Verkerke et al, 2021 ).…”

Section: The Neurovascular Unit: Function and Dysfunction In Stroke And Alzheimer’s Diseasementioning

confidence: 99%

“…Another essential function of astrocytes is glutamate uptake and release, which is very important for the maintenance of CNS homeostasis ( Dejakaisaya et al, 2021 ; van Putten et al, 2021 ; Verkerke et al, 2021 ). Astrocytes also have a critical role in the brain antioxidant system maintenance and in the production of glutathione, an important modulator of oxidative stress and aging ( Bains and Shaw, 1997 ; Venkateshappa et al, 2012 ; Howarth et al, 2017 ; Verkerke et al, 2021 ).…”

Section: The Neurovascular Unit: Function and Dysfunction In Stroke And Alzheimer’s Diseasementioning

confidence: 99%

Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer’s Disease and Stroke

Lemon

Canepa

Ilies

et al. 2021

Front. Aging Neurosci.

View full text Add to dashboard Cite

The Neurovascular Unit (NVU) is an important multicellular structure of the central nervous system (CNS), which participates in the regulation of cerebral blood flow (CBF), delivery of oxygen and nutrients, immunological surveillance, clearance, barrier functions, and CNS homeostasis. Stroke and Alzheimer Disease (AD) are two pathologies with extensive NVU dysfunction. The cell types of the NVU change in both structure and function following an ischemic insult and during the development of AD pathology. Stroke and AD share common risk factors such as cardiovascular disease, and also share similarities at a molecular level. In both diseases, disruption of metabolic support, mitochondrial dysfunction, increase in oxidative stress, release of inflammatory signaling molecules, and blood brain barrier disruption result in NVU dysfunction, leading to cell death and neurodegeneration. Improved therapeutic strategies for both AD and stroke are needed. Carbonic anhydrases (CAs) are well-known targets for other diseases and are being recently investigated for their function in the development of cerebrovascular pathology. CAs catalyze the hydration of CO2 to produce bicarbonate and a proton. This reaction is important for pH homeostasis, overturn of cerebrospinal fluid, regulation of CBF, and other physiological functions. Humans express 15 CA isoforms with different distribution patterns. Recent studies provide evidence that CA inhibition is protective to NVU cells in vitro and in vivo, in models of stroke and AD pathology. CA inhibitors are FDA-approved for treatment of glaucoma, high-altitude sickness, and other indications. Most FDA-approved CA inhibitors are pan-CA inhibitors; however, specific CA isoforms are likely to modulate the NVU function. This review will summarize the literature regarding the use of pan-CA and specific CA inhibitors along with genetic manipulation of specific CA isoforms in stroke and AD models, to bring light into the functions of CAs in the NVU. Although pan-CA inhibitors are protective and safe, we hypothesize that targeting specific CA isoforms will increase the efficacy of CA inhibition and reduce side effects. More studies to further determine specific CA isoforms functions and changes in disease states are essential to the development of novel therapies for cerebrovascular pathology, occurring in both stroke and AD.

show abstract

Physiological and Pathological Ageing of Astrocytes in the Human Brain

Cited by 34 publications

References 156 publications

The Aged Striatum: Evidence of Molecular and Structural Changes Using a Longitudinal Multimodal Approach in Mice

The Aged Striatum: Evidence of Molecular and Structural Changes Using a Longitudinal Multimodal Approach in Mice

Systematic review of human post‐mortem immunohistochemical studies and bioinformatics analyses unveil the complexity of astrocyte reaction in Alzheimer's disease

Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer’s Disease and Stroke

Contact Info

Product

Resources

About