Trends in Molecular Medicine
ReviewVSI: Focus on Glial Cells in Health and DiseaseAstrocyte Biomarkers in Alzheimer’s Disease
Section snippets
From Neurons to Astrocytes: Evolution of Alzheimer’s Disease Biomarkers
Our conceptualisation of Alzheimer’s disease (AD) may have reached a point where a paradigm shift is required. The disease is the most common cause of dementia worldwide [1], accounting for 50%–70% of all cases [2], but the most common subtype, sporadic AD, remains incompletely understood. It is undisputed that the deposition of amyloid-beta (Aβ) into Aβ plaques (see Glossary) and the formation of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein are the main
The Unique Role of Astrocytes in the Central Nervous System
Although incompletely understood, it is established that astrocytes and microglia are important regulators of central nervous system (CNS) inflammatory response, while oligodendrocytes provide support and insulation to axons [15]. Indeed, oligodendrocytes wrap axons with myelin, a coating of compacted cell membrane, which promotes electrical insulation and facilitates the transit of action potentials along axons. Glial cells have been implicated as contributors to AD pathophysiology with most
Reactive Astrocytes in Alzheimer’s Disease
In pathological situations, astrocytes undergo a series of morphological and functional alterations collectively referred as reactive astrocytes. Reactive astrocytes overexpress glial fibrillary acidic protein (GFAP) and vimentin and re-express nestin (usually expressed in immature astrocytes) [25]. These proteins are astrocytic cytoskeletal components called intermediate filaments (IFs). IFs are the third fibrous component of the cytoskeleton, in addition to microtubules and microfilaments,
Astrocytes and Microglial Cells: Partners in Neuroinflammatory Changes
Microglial activation has been extensively evaluated as an index of neuroinflammation in AD [16], but the neuroinflammatory contribution of astrocytes in AD is attracting more attention in the last years. A recent study demonstrates that reactive astrocytes are induced by activated microglia that release interleukin-1α (IL-1α), tumour necrosis factor-α (TNF-α), and complement component 1q (C1q), which induce phenotypic changes in astrocytes that assume a reactive neurotoxic form. The authors
Astrocytes Clearing, Degrading, Or Even Producing Amyloid-β
Studies have demonstrated that astrocytes have a major role in terms of clearing and degrading Aβ. In fact, Aβ enzymatic degrading proteases can be produced by reactive astrocytes. These proteases include neprilysin (NEP), endothelin-converting enzyme (ECE), insulin-degrading enzyme (IDE), and matrix metalloproteases. NEP, ECE, and IDE are metalloendopeptidases [42]. NEP exists mainly in cellular and intracellular plasma membrane of presynaptic neurons, but can be found in reactive astrocytes
Glutamatergic Excitotoxicity
Around 30 years ago, evidence of reduced astrocyte glutamatergic transport in AD, mainly dysfunctional activity of the glutamate transporters GLAST and GLT-1, was found in post-mortem tissue and is now corroborated by an extensive literature [56].
In AD brains and mouse models, immunocontent and mRNA expression of GLT-1 and GLAST are reduced 57, 58, 59, 60. Cultured human astrocytes from post-mortem AD parietal cortices also present decreased glutamate uptake, measured by ex vivo radioactivity
Abnormalities in Glucose Metabolism: The Contribution of Astrocytes
The dysfunction in glutamate homeostasis observed in AD is purported to contribute to glucose metabolism abnormalities. Glucose hypometabolism revealed by [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) is classically associated with AD and this phenomenon is characteristically linked to neuronal dysfunction [66]. Interestingly, according to the ANLS hypothesis, astrocytic glutamate uptake acts as one of the triggers signalling for glucose uptake by astrocytes 67, 68, 69, 70
Astrocytic Biomarkers in Alzheimer’s Disease
Sensitive and specific biomarkers already exist for the main pathological features of AD. In the A → T → N framework, Aβ and tau pathology can be assessed by measuring CSF concentrations of soluble Aβ and tau or fibrillar Aβ and tau with PET imaging; and neurodegeneration can be measured by [18F]FDG-PET or structural magnetic resonance imaging (MRI), as an index of brain atrophy. Typically, outcomes from these biomarkers are split into positive or negative results depending on a defined cutoff
Concluding Remarks
Astrocytes have complex roles at different stages of AD pathophysiology and the conceptualisation of AD is shifting to an integrative perspective in which neurons and astrocytes work intricately with each other. Astrocytes are involved in metabolic support of neurons, neurotransmission, neurotransmitter recycling, regulating CBF, and clearing and degrading Aβ. All these processes are dysfunctional in AD. Current AD therapies are completely focused on neuronal dysfunction (cholinergic or
Acknowledgements
L.P. receives financial support from the program IdEx Bordeaux ANR-10-IDEX-03-02. E.R.Z. receives financial support from CAPES (88881.141186/2017-01), CNPq (460172/2014-0), PRONEX, FAPERGS/CNPq (16/2551-0000475-7), Brazilian National Institute of Science and Technology in Excitotoxicity and Neuroprotection (465671/2014-4), and FAPERGS/MS/CNPq/SESRS-PPSUS (30786.434.24734.23112017). A.N. receives financial support from the Swedish Foundation for Strategic Research and Swedish Research Council
Glossary
- [11C]BU99008
- carbon-11-labelled positron emission tomography radiotracer that binds to the imidazoline2-binding site, highly expressed in astrocytes.
- [11C]-Deuterium-l-deprenyl ([11C]DED)
- carbon-11-labelled positron emission tomography radiotracer that binds to monoamine oxidase-B, mainly expressed in reactive astrocytes.
- Amyloid-β monomers
- amyloid-β peptide usually constituted of 40 or 42 amino acids.
- Amyloid-β oligomers
- soluble toxic amyloid-β species composed by amyloid monomers (ranging from 12 to
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