Review
VSI: Focus on Glial Cells in Health and Disease
Astrocyte Biomarkers in Alzheimer’s Disease

https://doi.org/10.1016/j.molmed.2018.11.006Get rights and content

Highlights

The neurocentric view of AD is evolving and the contributions astrocytes make to the disease’s pathological processes are finally considered.

AD pathology triggers astrocyte reactivity, which imaging and fluid biomarkers can measure in vivo.

Astrocyte dysfunction in AD could contribute to [18F]FDG-PET hypometabolism.

Astrocytes are promising targets for developing novel, specific fluid or imaging biomarkers for detecting preclinical AD.

Pharmacologically targeting astrocytes may lead to developing an effective treatment for AD.

Astrocytic contributions to Alzheimer’s disease (AD) progression were, until recently, largely overlooked. Astrocytes are integral to normal brain function and astrocyte reactivity is an early feature of AD, potentially providing a promising target for preclinical diagnosis and treatment. Several in vivo AD biomarkers already exist, but presently there is a paucity of specific and sensitive in vivo astrocyte biomarkers that can accurately measure preclinical AD. Measuring monoamine oxidase-B with neuroimaging and glial fibrillary acidic protein from bodily fluids are biomarkers that are currently available. Developing novel, more specific, and sensitive astrocyte biomarkers will make it possible to pharmaceutically target chemical pathways that preserve beneficial astrocytic functions in response to AD pathology. This review discusses astrocyte biomarkers in the context of AD.

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

References (179)

  • S. Nakagomi

    Endothelin-converting enzymes and endothelin receptor B messenger RNAs are expressed in different neural cell species and these messenger RNAs are coordinately induced in neurons and astrocytes respectively following nerve injury

    Neuroscience

    (2000)
  • N. Yamamoto

    Epigallocatechin gallate induces extracellular degradation of amyloid beta-protein by increasing neprilysin secretion from astrocytes through activation of ERK and PI3K pathways

    Neuroscience

    (2017)
  • J. Apelt

    Aging-related down-regulation of neprilysin, a putative beta-amyloid-degrading enzyme, in transgenic Tg2576 Alzheimer-like mouse brain is accompanied by an astroglial upregulation in the vicinity of beta-amyloid plaques

    Neurosci. Lett.

    (2003)
  • P. Yan

    Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ

    J. Biol. Chem.

    (2006)
  • S. Lesne

    Transforming growth factor-beta 1 potentiates amyloid-beta generation in astrocytes and in transgenic mice

    J. Biol. Chem.

    (2003)
  • J. Hardy

    Region-specific loss of glutamate innervation in Alzheimer’s disease

    Neurosci. Lett.

    (1987)
  • E. Masliah

    Abnormal glutamate transport function in mutant amyloid precursor protein transgenic mice

    Exp. Neurol.

    (2000)
  • J.D. Rothstein

    Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate

    Neuron

    (1996)
  • S. Huang

    Astrocytic glutamatergic transporters are involved in Abeta-induced synaptic dysfunction

    Brain Res.

    (2018)
  • K. Chen

    Characterizing Alzheimer’s disease using a hypometabolic convergence index

    Neuroimage

    (2011)
  • B. Voutsinos-Porche

    Glial glutamate transporters mediate a functional metabolic crosstalk between neurons and astrocytes in the mouse developing cortex

    Neuron

    (2003)
  • Y. Liu

    Decreased glucose transporters correlate to abnormal hyperphosphorylation of tau in Alzheimer disease

    FEBS Lett.

    (2008)
  • A. San Martin

    Nanomolar nitric oxide concentrations quickly and reversibly modulate astrocytic energy metabolism

    J. Biol. Chem.

    (2017)
  • P.J. Norris

    Neuronal nitric oxide synthase (nNOS) mRNA expression and NADPH-diaphorase staining in the frontal cortex, visual cortex and hippocampus of control and Alzheimer’s disease brains

    Brain Res. Mol. Brain Res.

    (1996)
  • K.J. Kwon

    Disruption of neuronal nitric oxide synthase dimerization contributes to the development of Alzheimer’s disease: involvement of cyclin-dependent kinase 5-mediated phosphorylation of neuronal nitric oxide synthase at Ser(293)

    Neurochem. Int.

    (2016)
  • A. Suzuki

    Astrocyte-neuron lactate transport is required for long-term memory formation

    Cell

    (2011)
  • H. Zetterberg et al.

    Fluid markers of traumatic brain injury

    Mol. Cell. Neurosci.

    (2015)
  • P. Mecocci

    Serum anti-GFAP and anti-S100 autoantibodies in brain aging, Alzheimer’s disease and vascular dementia

    J. Neuroimmunol.

    (1995)
  • F.J. Wolters et al.

    Epidemiology of dementia: the burden on society, the challenges for research

    Methods Mol. Biol.

    (2018)
  • H.W. Querfurth et al.

    Alzheimer’s disease

    N. Engl. J. Med.

    (2010)
  • J.C. Polanco

    Amyloid-beta and tau complexity – towards improved biomarkers and targeted therapies

    Nat. Rev. Neurol.

    (2018)
  • J.A. Hardy et al.

    Alzheimer’s disease: the amyloid cascade hypothesis

    Science

    (1992)
  • H. Zetterberg et al.

    Understanding the cause of sporadic Alzheimer’s disease

    Expert Rev. Neurother.

    (2014)
  • L.S. Honig

    Trial of solanezumab for mild dementia due to Alzheimer’s disease

    N. Engl. J. Med.

    (2018)
  • S. Salloway

    Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease

    N. Engl. J. Med.

    (2014)
  • S. Ostrowitzki

    A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease

    Alzheimers Res. Ther.

    (2017)
  • J. Sevigny

    Addendum: The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease

    Nature

    (2017)
  • G. McKhann

    Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease

    Neurology

    (1984)
  • N.J. Allen et al.

    Neuroscience: Glia – more than just brain glue

    Nature

    (2009)
  • S. Jakel et al.

    Glial cells and their function in the adult brain: a journey through the history of their ablation

    Front. Cell. Neurosci.

    (2017)
  • E.R. Zimmer

    Tracking neuroinflammation in Alzheimer’s disease: the role of positron emission tomography imaging

    J. Neuroinflammation

    (2014)
  • A. Verkhratsky et al.

    Physiology of astroglia

    Physiol. Rev.

    (2018)
  • M. Simard

    Signaling at the gliovascular interface

    J. Neurosci.

    (2003)
  • A.C. Luissint

    Tight junctions at the blood brain barrier: physiological architecture and disease-associated dysregulation

    Fluids Barriers CNS

    (2012)
  • L. Pellerin et al.

    Sweet sixteen for ANLS

    J. Cereb. Blood Flow Metab.

    (2012)
  • M.M. Halassa et al.

    Integrated brain circuits: astrocytic networks modulate neuronal activity and behavior

    Annu. Rev. Physiol.

    (2010)
  • E.E. Benarroch

    Glutamate transporters: diversity, function, and involvement in neurologic disease

    Neurology

    (2010)
  • U. Wilhelmsson

    Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury

    Proc. Natl. Acad. Sci. U. S. A.

    (2006)
  • M.A. McCall

    Targeted deletion in astrocyte intermediate filament (Gfap) alters neuronal physiology

    Proc. Natl. Acad. Sci. U. S. A.

    (1996)
  • D. Triolo

    Vimentin regulates peripheral nerve myelination

    Development

    (2012)
  • Cited by (196)

    View all citing articles on Scopus
    View full text