Astrocytes are highly efficient homeostatic glial cells playing a crucial role in optimal brain functioning and homeostasis. Astrocytes respond to changes in brain homoeostasis following central ...nervous system (CNS) injury/diseased state by a specific defence mechanism called reactive astrogliosis. Recent studies have implicated and placed reactive astrogliosis in the centre of pathophysiology of Alzheimer's disease (AD) and other neurodegenerative disorders. The AD biomarker field is evolving rapidly with new findings providing strong evidence which supports the notion that a reactive astrogliosis is an early event in the time course of AD progression which may precede other pathological hallmarks of AD. Clinical/translational in vivo PET and in vitro postmortem brain imaging studies demonstrated ‘a first and second wave’ of reactive astrogliosis in AD with distinct close‐loop relationships with other pathological biomarkers at different stages of the disease. At the end stages, reactive astrocytes are found to be associated, or in proximity, with amyloid plaque and tau pathological deposits in postmortem AD brains. Several new PET‐tracers, which are being in pipeline and validated at a very fast pace for mapping and visualising reactive astrogliosis in the brain, will provide further invaluable mechanistic insights into AD and other non‐AD dementia pathologies. The complementary roles of microglia and astrocyte activation in AD progression, along with the clinical value of new fluid astrocytes biomarkers in the context of existing biomarkers, are the latest avenue that needs further exploration.
Astrocytes are the key homeostatic cells in the human CNS, which responds to CNS injuries/diseased state by a specific defence mechanism called reactive astrogliosis. In Alzheimer's disease (AD), the role of astrocytes is still unclear and with new findings providing strong evidence that reactive astrogliosis is an early event in the time course of AD progression preceding some other pathological hallmarks. Based on clinical in vivo PET and post‐mortem brain imaging studies we propose ‘a first and second wave model’ of reactive astrogliosis in AD with distinct close loop relationships with soluble Aβ species and Aβ plaques as well as other hallmarks at different stages of the disease.
The ongoing search for therapeutic interventions in Alzheimer disease (AD) has highlighted the complexity of this condition and the need for additional biomarkers, beyond amyloid-β (Aβ) and tau, to ...improve clinical assessment. Astrocytes are brain cells that control metabolic and redox homeostasis, among other functions, and are emerging as an important focus of AD research owing to their swift response to brain pathology in the initial stages of the disease. Reactive astrogliosis - the morphological, molecular and functional transformation of astrocytes during disease - has been implicated in AD progression, and the definition of new astrocytic biomarkers could help to deepen our understanding of reactive astrogliosis along the AD continuum. As we highlight in this Review, one promising biomarker candidate is the astrocytic α7 nicotinic acetylcholine receptor (α7nAChR), upregulation of which correlates with Aβ pathology in the brain of individuals with AD. We revisit the past two decades of research into astrocytic α7nAChRs to shed light on their roles in the context of AD pathology and biomarkers. We discuss the involvement of astrocytic α7nAChRs in the instigation and potentiation of early Aβ pathology and explore their potential as a target for future reactive astrocyte-based therapeutics and imaging biomarkers in AD.
A substantial fraction of coronavirus disease 2019 (COVID-19) patients experience neurological manifestations. Nevertheless, brain changes caused by severe acute respiratory syndrome coronavirus 2 ...(SARS-CoV-2) remain largely unknown. Here, we provide a brief overview of positron emission tomography (PET) applications that could advance current understanding of CNS pathophysiological alterations associated with SARS-CoV-2 infection.
Amyloid‐β (Aβ) dysmetabolism is tightly associated with pathological processes in Alzheimer's disease (AD). Currently, it is thought that, in addition to Aβ fibrils that give rise to plaque ...formation, Aβ aggregates into non‐fibrillar soluble oligomers (AβOs). Soluble AβOs have been extensively studied for their synaptotoxic and neurotoxic properties. In this review, we discuss physicochemical properties of AβOs and their impact on different brain cell types in AD. Additionally, we summarize three decades of studies with AβOs, providing a compelling bulk of evidence regarding cell‐specific mechanisms of toxicity. Cellular models may lead us to a deeper understanding of the detrimental effects of AβOs in neurons and glial cells, putatively shedding light on the development of innovative therapies for AD.
Amyloid‐beta oligomers (AβOs) are synaptotoxins in Alzheimer's disease (AD) and have been firstly characterized in the 90s. Since mechanisms are not fully elucidated, cell culture may hold the key for better understanding AβOs toxic roles in AD pathophysiology. In this review, we briefly revisit AβOs physicochemical properties and toxic mechanism by discussing three decades of research in AβOs cellular models.
The excitatory amino acid transporter 2 (EAAT2) plays a key role in the clearance and recycling of glutamate - the major excitatory neurotransmitter in the mammalian brain. EAAT2 loss/dysfunction ...triggers a cascade of neurodegenerative events, comprising glutamatergic excitotoxicity and neuronal death. Nevertheless, our current knowledge regarding EAAT2 in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD), is restricted to post-mortem analysis of brain tissue and experimental models. Thus, detecting EAAT2 in the living human brain might be crucial to improve diagnosis/therapy for ALS and AD. This perspective article describes the role of EAAT2 in physio/pathological processes and provides a structure–activity relationship of EAAT2-binders, bringing two perspectives: therapy (activators) and diagnosis (molecular imaging tools).
A monoamine oxidase B (MAO-B) selective positron emission tomography (PET) tracer 11C-deuterium-l-deprenyl holds promise for imaging reactive astrogliosis in neurodegenerative diseases, such as ...Alzheimer′s disease (AD). Two novel PET tracers (11C-BU99008 and 18F-SMBT-1) have recently been developed to assess the complexity of reactive astrogliosis in the AD continuum. We have investigated the binding properties of SMBT-1, l-deprenyl, and BU99008 in AD and cognitively normal control (CN) brains. Competition binding assays with 3H-l-deprenyl and 3H-BU99008 versus unlabeled SMBT-1 in postmortem AD and CN temporal and frontal cortex brains demonstrated that SMBT-1 interacted with 3H-deprenyl at a single binding site (nM range) and with 3H-BU99008 at multiple binding sites (from nM to μM). Autoradiography studies on large frozen postmortem AD and CN hemisphere brain sections demonstrated that 1 μM SMBT-1 almost completely displaced the 3H-l-deprenyl binding (>90%), while SMBT-1 only partly displaced the 3H-BU99008 binding (50–60% displacement) in cortical regions. In conclusion, SMBT-1, l-deprenyl, and BU99008 interact at the same MAO-B binding site, while BU99008 shows an additional independent binding site in AD and CN brains. The high translational power of our studies in human AD and CN brains suggests that the multitracer approach with SMBT-1, l-deprenyl, and BU99008 could be useful for imaging reactive astrogliosis.
Purpose
Advances in functional imaging allowed us to visualize brain glucose metabolism in vivo and non-invasively with
18
Ffluoro-2-deoxyglucose (FDG) positron emission tomography (PET) imaging. In ...the past decades, FDG-PET has been instrumental in the understanding of brain function in health and disease. The source of the FDG-PET signal has been attributed to neuronal uptake, with hypometabolism being considered as a direct index of neuronal dysfunction or death. However, other brain cells are also metabolically active, including astrocytes. Based on the astrocyte-neuron lactate shuttle hypothesis, the activation of the glutamate transporter 1 (GLT-1) acts as a trigger for glucose uptake by astrocytes. With this in mind, we investigated glucose utilization changes after pharmacologically downregulating GLT-1 with clozapine (CLO), an anti-psychotic drug.
Methods
Adult male Wistar rats (control,
n
= 14; CLO,
n
= 12) received CLO (25/35 mg kg
−1
) for 6 weeks. CLO effects were evaluated in vivo with FDG-PET and cortical tissue was used to evaluate glutamate uptake and GLT-1 and GLAST levels. CLO treatment effects were also assessed in cortical astrocyte cultures (glucose and glutamate uptake, GLT-1 and GLAST levels) and in cortical neuronal cultures (glucose uptake).
Results
CLO markedly reduced in vivo brain glucose metabolism in several brain areas, especially in the cortex. Ex vivo analyses demonstrated decreased cortical glutamate transport along with GLT-1 mRNA and protein downregulation. In astrocyte cultures, CLO decreased GLT-1 density as well as glutamate and glucose uptake. By contrast, in cortical neuronal cultures, CLO did not affect glucose uptake.
Conclusion
This work provides in vivo demonstration that GLT-1 downregulation induces astrocyte-dependent cortical FDG-PET hypometabolism—mimicking the hypometabolic signature seen in people developing dementia—and adds further evidence that astrocytes are key contributors of the FDG-PET signal.
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