Skip to main content
SpringerLink
Log in

Traversing Through the Trajectory of Pathogenic Astrocytes in Alzheimer’s Disease

  • Chapter
  • First Online:
Deciphering Drug Targets for Alzheimer’s Disease

  • 231 Accesses

Abstract

Alzheimer’s disease (AD) is a prevalent and debilitating neurological condition with no curable therapies in the pipeline. Alzheimer’s disease-related neurodegeneration negatively influences various brain cells, including astrocytes, neurons, and microglia. Interactions between healthy neural cell types and AD hallmarks: Aβ plaques and tau fibril deposits have been shown to produce detrimental cellular stresses and deterioration in brain functions. Astrocytes help to regulate nutritional balance, cerebral blood flow, tissue healing, and the blood–brain barrier. They engage in the CNS’s inflammatory/immune responses. Evidence also suggests that astrocytes have neuroprotective and neurotoxic effects based on the disease stage and microenvironment. Changes in astrocyte function have been observed in individuals with early-onset Alzheimer’s disease, displaying disproportions in gliotransmission, neurotransmitter homeostasis, astroglial atrophy, disruptions in synaptic associations, neuroinflammation, and neurodegeneration. Moreover, the presence of Aβ plaques appears to impact astrocytes, affecting calcium levels and pro-inflammatory activity via RAGE-NF-kB pathway. The conventional treatment approaches for AD-related neuropathology are not anticipated to be comprehensive. The rationale for this may be that AD treatment involves a therapeutic strategy to minimize its cascading recurrence, and most drugs are inefficient at developing effective responses. Hence, researchers are keen on exploring the roles of astrocytes and their molecular pathways to identify potent therapies in AD. This review provides a broad approach, emphasizing the roles of astrocytes in healthy brains and their pathological changes in AD, as well as potential astrocyte-related therapy regimens. Novel strategies comprising astrocytes and aimed at alleviating oxidative stress and neuroinflammation in AD have also been presented.

Graphical Abstract

An illustration of Alzheimer’s disease with neuropathological implications. The labeled details include activated microglia, injured reactive astrocytes, the release of proinflammatory signals, dysregulations in vasoactivity, and cellular apoptosis.

The graphical abstract demonstrates the neuropathological implications of Alzheimer’s disease on several neural sub-populations, i.e. neurons, astrocytes, microglia, and oligodendrocytes.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

Abbreviations

2 ERK:

Extracellular signal-regulated kinase

ABCC1:

ATP-binding cassette subfamily C member 1

AD:

Alzheimer’s disease

AICD:

Amyloid precursor protein intracellular domain

ALS:

Amyotrophic lateral sclerosis

AMPA:

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor

APP:

Amyloid precursor protein

ATP:

Adenosine triphosphate

Aβ:

Amyloid-beta

B CN:

Calcineurin

BBB:

Blood–brain barrier

BMP:

Bone morphogenetic proteins

CBF:

Cerebral blood flow

CFB:

Complement factor

CNS:

Central nervous system

CNTF:

Ciliary neurotrophic factor

Cx43:

Gap junction alpha-1 protein

DAM:

Disease-associated macrophages

DG:

Dentate gyrate

EAAT2:

Excitatory amino acid transporter

EGFR:

Epidermal growth factor receptor

GABA:

Gamma-aminobutyric acid

GFAP:

Glial fibrillary acidic protein

GH:

Growth hormone

GLAST1:

Glutamate transporter

GLT-1:

l-glutamate transporter

GSH:

Glutathione

GSK3β:

Glycogen synthase kinase-3 beta

HMGB1:

High mobility group box 1 protein

IkB-α:

Nuclear factor of kappa light polypeptide gene enhancer in B-cell inhibitor

ILGF-1:

Insulin-like growth factor 1

JAK:

Janus kinase

LRPs:

Lipoprotein receptor-related protein

MAO-B:

Monoamine oxidase B

MAP-2:

Microtubule-associated protein 2

MEK1/MAP2K:

Mitogen-activated protein kinase

MMP:

Mitochondrial membrane potential

MX1S:

MX dynamin-like GTPase 1

MyD88:

Myeloid differentiation primary response 88

NADPH:

Reduced nicotinamide adenine dinucleotide phosphate

NFAT:

Nuclear factor of activated T cells

NF-kB:

Nuclear factor kappa B

NFTs:

Interneuronal neurofibrillary tangles

NICD:

Notch intracellular domain

NMDAR:

N-methyl-D-aspartate receptor

NOTCH:

Notch homolog 1, translocation-associated

NOX:

NADPH-oxidized

NPCs:

Neural precursor cells

NRF2:

Nuclear factor-erythroid factor 2-related factor 2

NSCs:

Neural stem cells

OXPHOS:

Oxidative phosphorylation

PAR:

Poly(ADP-ribose) polymers

PARP:

Poly (ADP-ribose) polymerase-1

PD:

Parkinson’s disease

PGC-1α:

Peroxisome proliferator-activated receptor-gamma coactivator

PHF:

Paired helical fragments

ptau:

Phosphorylated tau

RAGE:

Receptor for advanced glycation end products

RBP-J:

Recombination signal binding protein for immunoglobulin kappa J region

ROCK inhibitor:

Rho-kinase inhibitor

ROS:

Reactive oxygen species

R-SMADs:

Receptor-regulated Smads

S100B:

S100 calcium-binding protein B

sAPP-β:

Soluble amyloid precursor protein beta

SGZ:

Sub-granular zones

sNMDAR:

Synaptic N-methyl-D-aspartate receptor

SOCS3:

Suppressor of cytokine signalling 3

SR:

Scavenger receptor

STAT:

Signal transducer and activator of transcription

TFAM:

Mitochondrial transcription factor A

TG:

Transgenic mice

TGIF:

Transforming growth-interacting factor

TLR4:

Toll-like receptor 4

TNF-α:

Tumour necrosis factor alpha

TRF:

Thyrotropin-releasing factor

TTP:

Alpha-tocopherol transfer protein

U.S. FDA:

United States Food and Drug Administration

V-SVZ:

Ventricular–sub-ventricular zones

α-TCP:

Alpha-tocopherol

References

  • Abeti R, Abramov AY, Duchen MR (2011) Beta-amyloid activates PARP causing astrocytic metabolic failure and neuronal death. Brain 134(Pt 6):1658–1672

    Article  PubMed  Google Scholar 

  • Abramov AY, Canevari L, Duchen MR (2004) Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J Neurosci 24(2):565–575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Abramov AY, Jacobson J, Wientjes F, Hothersall J, Canevari L, Duchen MR (2005) Expression and modulation of an NADPH oxidase in mammalian astrocytes. J Neurosci 25(40):9176–9184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Acaz-Fonseca E, Ortiz-Rodriguez A, Azcoitia I et al (2019) Notch signaling in astrocytes mediates their morphological response to an inflammatory challenge. Cell Death Dis 5:85

    Article  Google Scholar 

  • Alberdi E, Wyssenbach A, Alberdi M, Sánchez-Gómez MV, Cavaliere F, Rodríguez JJ, Verkhratsky A, Matute C (2013) Ca(2+)-dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid β-treated astrocytes and in a model of Alzheimer’s disease. Aging Cell 12(2):292–302

    Article  CAS  PubMed  Google Scholar 

  • Alves VS, Alves-Silva HS, Orts DJB, Ribeiro-Silva L, Arcisio-Miranda M, Oliveira FA (2019) Calcium signaling in neurons and glial cells: role of cav1 channels. Neuroscience 421:95–111

    Article  CAS  PubMed  Google Scholar 

  • Angulo MC, Le Meur K, Kozlov AS, Charpak S, Audinat E (2008) GABA, a forgotten gliotransmitter. Prog Neurobiol 86(3):297–303

    Article  CAS  PubMed  Google Scholar 

  • Arai H, Lee VM, Messinger ML, Greenberg BD, Lowery DE, Trojanowski JQ (1991) Expression patterns of beta-amyloid precursor protein (beta-APP) in neural and nonneural human tissues from Alzheimer’s disease and control subjects. Ann Neurol 30(5):686–693

    Article  CAS  PubMed  Google Scholar 

  • Araque A, Parpura V, Sanzgiri RP, Haydon PG (1999) Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 22(5):208–215

    Article  CAS  PubMed  Google Scholar 

  • Araque A, Carmignoto G, Haydon PG, Oliet SH, Robitaille R, Volterra A (2014) Gliotransmitters travel in time and space. Neuron 81(4):728–739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arendt T, Stieler JT, Holzer M (2016) Tau and tauopathies. Brain Res Bull 126(Pt 3):238–292

    Article  CAS  PubMed  Google Scholar 

  • Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen GW (1991) The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer’s disease. Cereb Cortex 1(1):103–116

    Article  CAS  PubMed  Google Scholar 

  • Arriza JL, Fairman WA, Wadiche JI, Murdoch GH, Kavanaugh MP, Amara SG (1994) Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex. J Neurosci 14(9):5559–5569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bezzi P, Carmignoto G, Pasti L, Vesce S, Rossi D, Rizzini BL, Pozzan T, Volterra A (1998) Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 391(6664):281–285

    Article  CAS  PubMed  Google Scholar 

  • Böck MC, Höfner G, Wanner KT (2020) N-Substituted nipecotic acids as (S)-SNAP-5114 analogues with modified lipophilic domains. ChemMedChem 15(9):756–771

    Article  PubMed  PubMed Central  Google Scholar 

  • Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82(4):239–259

    Article  CAS  PubMed  Google Scholar 

  • Bragdon B, Moseychuk O, Saldanha S, King D, Julian J, Nohe A (2011) Bone morphogenetic proteins: a critical review. Cell Signal 23(4):609–620

    Article  CAS  PubMed  Google Scholar 

  • Bürkle A (2005) Poly(ADP-ribose). The most elaborate metabolite of NAD+. FEBS J 272(18):4576–4589

    Article  PubMed  Google Scholar 

  • Canas PM, Porciúncula LO, Cunha GM, Silva CG, Machado NJ, Oliveira JM, Oliveira CR, Cunha RA (2009) Adenosine A2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by beta-amyloid peptides via p38 mitogen-activated protein kinase pathway. J Neurosci 29(47):14741–14751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cao F, Hata R, Zhu P, Ma YJ, Tanaka J, Hanakawa Y, Hashimoto K, Niinobe M, Yoshikawa K, Sakanaka M (2006) Overexpression of SOCS3 inhibits astrogliogenesis and promotes maintenance of neural stem cells. J Neurochem 98(2):459–470

    Article  CAS  PubMed  Google Scholar 

  • Carbone M, Duty S, Rattray M (2012) Riluzole elevates GLT-1 activity and levels in striatal astrocytes. Neurochem Int 60(1):31–38

    Article  CAS  PubMed  Google Scholar 

  • Chay KO, Nam Koong KY, Hwang S, Kim JK, Bae CS (2017) NADPH oxidase mediates β-amyloid peptide-induced neuronal death in mouse cortical cultures. Chonnam Med J 53(3):196–202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen S, Luo M, Zhao Y, Zhang Y, He M, Cai W, Liu A (2015) Fasudil stimulates neurite outgrowth and promotes differentiation in C17.2 neural stem cells by modulating notch signalling but not autophagy. Cell Physiol Biochem 36(2):531–541

    Article  CAS  PubMed  Google Scholar 

  • Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65(1):1–105

    Article  CAS  PubMed  Google Scholar 

  • Darnell JE Jr, Kerr IM, Stark GR (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264(5164):1415–1421

    Article  CAS  PubMed  Google Scholar 

  • DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27(5):457–464

    Article  CAS  PubMed  Google Scholar 

  • Delekate A, Füchtemeier M, Schumacher T et al (2014) Metabotropic P2Y1 receptor signalling mediates astrocytic hyperactivity in vivo in an Alzheimer’s disease mouse model. Nat Commun 5:5422

    Article  PubMed  Google Scholar 

  • Ebneth A, Godemann R, Stamer K, Illenberger S, Trinczek B, Mandelkow E (1998) Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer’s disease. J Cell Biol 143(3):777–794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Emsley JG, Macklis JD (2006) Astroglial heterogeneity closely reflects the neuronal-defined anatomy of the adult murine CNS. Neuron Glia Biol 2(3):175–186

    Article  PubMed  PubMed Central  Google Scholar 

  • Fatoba O, Itokazu T, Yamashita T (2021) Complement cascade functions during brain development and neurodegeneration. FEBS J 289(8):2085–2109

    Article  PubMed  Google Scholar 

  • Floyd RA, Carney JM (1992) Free radical damage to protein and DNA: mechanisms involved and relevant observations on brain undergoing oxidative stress. Ann Neurol 32(Suppl):22–27

    Article  Google Scholar 

  • Foster JB, Lashley R, Zhao F, Wang X, Kung N, Askwith CC, Lin L, Shultis MW, Hodgetts KJ, Lin CG (2019) Enhancement of tripartite synapses as a potential therapeutic strategy for Alzheimer’s disease: a preclinical study in rTg4510 mice. Alzheimers Res Ther 11(1):75

    Article  PubMed  PubMed Central  Google Scholar 

  • Fratiglioni L, De Ronchi D, Agüero-Torres H (1999) Worldwide prevalence and incidence of dementia. Drugs Aging 15(5):365–375

    Article  CAS  PubMed  Google Scholar 

  • Fridovich I (1999) Fundamental aspects of reactive oxygen species, or what’s the matter with oxygen? Ann N Y Acad Sci 893:13–18

    Article  CAS  PubMed  Google Scholar 

  • Furman JL, Norris CM (2014) Calcineurin and glial signaling: neuroinflammation and beyond. J Neuroinflammation 11:158

    Article  PubMed  PubMed Central  Google Scholar 

  • Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L et al (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349(6311):704–706

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez-Reyes RE, Rubiano MG (2018) Astrocyte’s RAGE: more than just a question of mood. Cent Nerv Syst Agents Med Chem 18(1):39–48

    Article  CAS  PubMed  Google Scholar 

  • Guo MF, Zhang HY, Li YH, Gu QF, Wei WY, Wang YY, Zhang XJ, Liu XQ, Song LJ, Chai Z, Yu JZ, Ma CG (2020) Fasudil inhibits the activation of microglia and astrocytes of transgenic Alzheimer’s disease mice via the downregulation of TLR4/Myd88/NF-κB pathway. J Neuroimmunol 346:577284

    Article  CAS  PubMed  Google Scholar 

  • Gupta S, Mishra K, Surolia A, Banerjee K (2011) Suppressor of cytokine signalling-6 promotes neurite outgrowth via JAK2/STAT5-mediated signalling pathway, involving negative feedback inhibition. PLoS One 6(11):e26674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hefendehl J, LeDue J, Ko R et al (2016) Mapping synaptic glutamate transporter dysfunction in vivo to regions surrounding Aβ plaques by iGluSnFR two-photon imaging. Nat Commun 7:13441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heneka MT, Carson MJ, El Khoury J, Landreth GE et al (2015) Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14(4):388–405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Henstridge CM, Tzioras M, Paolicelli RC (2019) Glial contribution to excitatory and inhibitory synapse loss in neurodegeneration. Front Cell Neurosci 13:63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Herceg Z, Wang ZQ (2001) Functions of poly(ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. Mutat Res 477(1-2):97–110

    Article  CAS  PubMed  Google Scholar 

  • Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, Avila C, Kambham N, Bierhaus A, Nawroth P, Neurath MF, Slattery T, Beach D, McClary J, Nagashima M, Morser J, Stern D, Schmidt AM (1999) RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 97(7):889–901

    Article  CAS  PubMed  Google Scholar 

  • Hori O, Brett J, Slattery T, Cao R, Zhang J, Chen JX, Nagashima M, Lundh ER, Vijay S, Nitecki D et al (1995) The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J Biol Chem 270(43):25752–25761

    Article  CAS  PubMed  Google Scholar 

  • Huang Y, Mucke L (2012) Alzheimer mechanisms and therapeutic strategies. Cell 148(6):1204–1222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ioannou MS, Jackson J, Sheu SH, Chang CL, Weigel AV, Liu H, Pasolli HA, Xu CS, Pang S, Matthies D, Hess HF, Lippincott-Schwartz J, Liu Z (2019) Neuron-astrocyte metabolic coupling protects against activity-induced fatty acid toxicity. Cell 177(6):1522–1535

    Article  CAS  PubMed  Google Scholar 

  • Itoh S, Itoh F, Goumans MJ, Ten Dijke P (2000) Signaling of transforming growth factor-beta family members through Smad proteins. Eur J Biochem 267(24):6954–6967

    Article  CAS  PubMed  Google Scholar 

  • Jacob CP, Koutsilieri E, Bartl J, Neuen-Jacob E, Arzberger T, Zander N, Ravid R, Roggendorf W, Riederer P, Grünblatt E (2007) Alterations in expression of glutamatergic transporters and receptors in sporadic Alzheimer’s disease. J Alzheimers Dis 11(1):97–116

    Article  CAS  PubMed  Google Scholar 

  • Jäkel S, Dimou L (2017) Glial cells and their function in the adult brain: a journey through the history of their ablation. Front Cell Neurosci 11:24

    Article  PubMed  PubMed Central  Google Scholar 

  • Jessen KR (2004) Glial cells. Int J Biochem Cell Biol 36(10):1861–1867. https://doi.org/10.1016/j.biocel.2004.02.023

    Article  CAS  PubMed  Google Scholar 

  • Jo S, Yarishkin O, Hwang YJ, Chun YE et al (2014) GABA from reactive astrocytes impairs memory in mouse models of Alzheimer’s disease. Nat Med 20(8):886–896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaniyappan S, Chandupatla RR, Mandelkow EM, Mandelkow E (2017) Extracellular low-n oligomers of tau cause selective synaptotoxicity without affecting cell viability. Alzheimers Dement 13(11):1270–1291

    Article  PubMed  Google Scholar 

  • Karran E, Mercken M, De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10(9):698–712

    Article  CAS  PubMed  Google Scholar 

  • Khan MI, Hasan F, Hasan Al Mahmud KA, Adnan A (2021) Domain focused and residue focused phosphorylation effect on tau protein: a molecular dynamics simulation study. J Mech Behav Biomed Mater 113:104149

    Article  CAS  PubMed  Google Scholar 

  • Kidd M (1963) Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature 197:192–193

    Article  CAS  PubMed  Google Scholar 

  • Kriegstein A, Alvarez-Buylla A (2009) The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci 32:149–184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuchibhotla KV, Lattarulo CR, Hyman BT, Bacskai BJ (2009) Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science 323(5918):1211–1215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lang R, Pauleau AL, Parganas E, Takahashi Y, Mages J, Ihle JN, Rutschman R, Murray PJ (2003) SOCS3 regulates the plasticity of gp130 signaling. Nat Immunol 4(6):546–550

    Article  CAS  PubMed  Google Scholar 

  • Larson EB, Kukull WA, Katzman RL (1992) Cognitive impairment: dementia and Alzheimer’s disease. Annu Rev Public Health 13:431–449

    Article  CAS  PubMed  Google Scholar 

  • Lau CL, O’Shea RD, Broberg BV, Bischof L, Beart PM (2011) The Rho kinase inhibitor Fasudil up-regulates astrocytic glutamate transport subsequent to actin remodelling in murine cultured astrocytes. Br J Pharmacol 163(3):533–545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laurence A, Pesu M, Silvennoinen O, O'Shea J (2012) JAK kinases in health and disease: an update. Open Rheumatol J 6:232–244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lehre KP, Danbolt NC (1998) The number of glutamate transporter subtype molecules at glutamatergic synapses: chemical and stereological quantification in young adult rat brain. J Neurosci 18(21):8751–8757

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li T, Chen X, Zhang C, Zhang Y, Yao W (2019) An update on reactive astrocytes in chronic pain. J Neuroinflammation 16(1):140

    Article  PubMed  PubMed Central  Google Scholar 

  • Lian H, Yang L, Cole A, Sun L, Chiang AC, Fowler SW, Shim DJ, Rodriguez-Rivera J, Taglialatela G, Jankowsky JL, Lu HC, Zheng H (2015) NFκB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer’s disease. Neuron 85(1):101–115

    Article  CAS  PubMed  Google Scholar 

  • Liddelow SA (2019) Modern approaches to investigating non-neuronal aspects of Alzheimer’s disease. FASEB J 33(2):1528–1535

    Article  CAS  PubMed  Google Scholar 

  • Lim DA, Alvarez-Buylla A (2016) The adult ventricular-subventricular zone (V-SVZ) and olfactory bulb (OB) neurogenesis. Cold Spring Harb Perspect Biol 8(5):a018820

    Article  PubMed  PubMed Central  Google Scholar 

  • Lim D, Iyer A, Ronco V, Grolla AA, Canonico PL, Aronica E, Genazzani AA (2013) Amyloid beta deregulates astroglial mGluR5-mediated calcium signaling via calcineurin and Nf-kB. Glia 61(7):1134–1145

    Article  PubMed  Google Scholar 

  • Love S, Barber R, Wilcock GK (1999) Increased poly(ADP-ribosyl)ation of nuclear proteins in Alzheimer’s disease. Brain 122(Pt 2):247–253

    Article  PubMed  Google Scholar 

  • Luna-Muñoz J, Chávez-Macías L, García-Sierra F, Mena R (2007) Earliest stages of tau conformational changes are related to the appearance of a sequence of specific phospho-dependent tau epitopes in Alzheimer’s disease. J Alzheimers Dis 12(4):365–375

    Article  PubMed  Google Scholar 

  • Martínez-Zamudio RI, Ha HC (2014) PARP1 enhances inflammatory cytokine expression by alteration of promoter chromatin structure in microglia. Brain Behav 4(4):552–565

    Article  PubMed  PubMed Central  Google Scholar 

  • Martire S, Mosca L, d'Erme M (2015) PARP-1 involvement in neurodegeneration: a focus on Alzheimer’s and Parkinson’s diseases. Mech Ageing Dev 146-148:53–64

    Article  CAS  PubMed  Google Scholar 

  • Masliah E, Terry RD, DeTeresa RM, Hansen LA (1989) Immunohistochemical quantification of the synapse-related protein synaptophysin in Alzheimer disease. Neurosci Lett 103(2):234–239

    Article  CAS  PubMed  Google Scholar 

  • Matyash V, Kettenmann H (2010) Heterogeneity in astrocyte morphology and physiology. Brain Res Rev 63(1-2):2–10

    Article  CAS  PubMed  Google Scholar 

  • Meffert MK, Chang JM, Wiltgen BJ, Fanselow MS, Baltimore D (2003) NF-kappa B functions in synaptic signaling and behavior. Nat Neurosci 6(10):1072–1078

    Article  CAS  PubMed  Google Scholar 

  • Meraz-Ríos MA, Lira-De León KI, Campos-Peña V, De Anda-Hernández MA, Mena-López R (2010) Tau oligomers and aggregation in Alzheimer’s disease. J Neurochem 112(6):1353–1367

    Article  PubMed  Google Scholar 

  • Morrison SJ, Perez SE, Qiao Z, Verdi JM, Hicks C, Weinmaster G, Anderson DJ (2000) Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells. Cell 101(5):499–510

    Article  CAS  PubMed  Google Scholar 

  • Murgas P, Godoy B, von Bernhardi R (2012) Aβ potentiates inflammatory activation of glial cells induced by scavenger receptor ligands and inflammatory mediators in culture. Neurotox Res 22(1):69–78

    Article  CAS  PubMed  Google Scholar 

  • Nagele RG, Wegiel J, Venkataraman V, Imaki H, Wang KC (2004) Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease. Neurobiol Aging 25:663–674

    Article  CAS  PubMed  Google Scholar 

  • Nakashima K, Yanagisawa M, Arakawa H, Kimura N, Hisatsune T, Kawabata M, Miyazono K, Taga T (1999) Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science 284(5413):479–482

    Article  CAS  PubMed  Google Scholar 

  • Nicolas CS, Amici M, Bortolotto ZA, Doherty A, Csaba Z, Fafouri A, Dournaud P, Gressens P, Collingridge GL, Peineau S (2013) The role of JAK-STAT signaling within the CNS. JAKSTAT 2(1):e22925

    PubMed  PubMed Central  Google Scholar 

  • Oberheim NA, Goldman SA, Nedergaard M (2012) Heterogeneity of astrocytic form and function. Methods Mol Biol 814:23–45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okamoto M, Gray JD, Larson CS, Kazim SF, Soya H, McEwen BS, Pereira AC (2019) Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer’s disease. Transl Psychiatry 8(1):153

    Article  Google Scholar 

  • Oyinbo CA (2011) Secondary injury mechanisms in traumatic spinal cord injury: a nugget of this multiply cascade. Acta Neurobiol Exp 71(2):281–299

    Google Scholar 

  • Park JH, Ju YH, Choi JW, Song HJ et al (2019) Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer’s disease. Sci Adv 5(3):eaav0316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perea G, Navarrete M, Araque A (2009) Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci 232(8):421–431

    Article  Google Scholar 

  • Perrig WJ, Perrig P, Stähelin HB (1997) The relation between antioxidants and memory performance in the old and very old. J Am Geriatr Soc 45(6):718–724

    Article  CAS  PubMed  Google Scholar 

  • Piccinin GL, Finali G, Piccirilli M (1990) Neuropsychological effects of L-deprenyl in Alzheimer’s type dementia. Clin Neuropharmacol 13(2):147–163

    Article  CAS  PubMed  Google Scholar 

  • Pleiss MM, Sompol P, Kraner SD, Abdul HM, Furman JL, Guttmann RP, Wilcock DM, Nelson PT, Norris CM (2016) Calcineurin proteolysis in astrocytes: Implications for impaired synaptic function. Biochim Biophys Acta 1862(9):1521–1532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J (2006) Synapse formation and function is modulated by the amyloid precursor protein. J Neurosci 26(27):7212–7221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qin B, Cartier L, Dubois-Dauphin M, Li B, Serrander L, Krause KH (2006) A key role for the microglial NADPH oxidase in APP-dependent killing of neurons. Neurobiol Aging 27(11):1577–1587

    Article  CAS  PubMed  Google Scholar 

  • Rojo LE, Fernandez JA, Maccioni AA, Jimenez JM, Maccioni RB (2008) Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer’s disease. Arch Med Res 39:1–16

    Article  CAS  PubMed  Google Scholar 

  • Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW, Kanai Y, Hediger MA, Wang Y, Schielke JP, Welty DF (1996) Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16(3):675–686

    Article  CAS  PubMed  Google Scholar 

  • Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS, Toan SV, Bruijn LI, Su ZZ, Gupta P, Fisher PB (2005) Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433(7021):73–77

    Article  CAS  PubMed  Google Scholar 

  • Sarlus H, Heneka MT (2017) Microglia in Alzheimer’s disease. J Clin Invest 127(9):3240–3249

    Article  PubMed  PubMed Central  Google Scholar 

  • Selvaraju TR, Khaza'ai H, Vidyadaran S, Abd Mutalib MS, Vasudevan R (2014) The neuroprotective effects of tocotrienol rich fraction and alpha tocopherol against glutamate injury in astrocytes. Bosn J Basic Med Sci 14(4):195–204

    PubMed  PubMed Central  Google Scholar 

  • Sheng B, Wang X, Su B, Lee HG, Casadesus G, Perry G, Zhu X (2012) Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in Alzheimer’s disease. J Neurochem 120(3):419–429

    Article  CAS  PubMed  Google Scholar 

  • Small GW, Rabins PV, Barry PP, Buckholtz NS, DeKosky ST, Ferris SH, Finkel SI, Gwyther LP, Khachaturian ZS, Lebowitz BD, McRae TD, Morris JC, Oakley F, Schneider LS, Streim JE, Sunderland T, Teri LA, Tune LE (1997) Diagnosis and treatment of Alzheimer disease and related disorders. Consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer’s Association, and the American Geriatrics Society. JAMA 278(16):1363–1371

    Article  CAS  PubMed  Google Scholar 

  • Sriram K, Benkovic SA, Hebert MA, Miller DB, O'Callaghan JP (2004) Induction of gp130- related cytokines and activation of JAK2/STAT3 pathway in astrocytes precedes up-regulation of glial fibrillary acidic protein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of neurodegeneration: key signaling pathway for astrogliosis in vivo? J Biol Chem 279(19):19936–19947

    Article  CAS  PubMed  Google Scholar 

  • Szabó C, Ohshima H (1997) DNA damage induced by peroxynitrite: subsequent biological effects. Nitric Oxide 1(5):373–385

    Article  PubMed  Google Scholar 

  • Takahashi K, Kong Q, Lin Y, Stouffer N, Schulte DA, Lai L, Liu Q, Chang LC, Dominguez S, Xing X, Cuny GD, Hodgetts KJ, Glicksman MA, Lin CL (2015) Restored glial glutamate transporter EAAT2 function as a potential therapeutic approach for Alzheimer’s disease. J Exp Med 212(3):319–332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takizawa T, Nakashima K, Namihira M, Ochiai W, Uemura A, Yanagisawa M, Fujita N, Nakao M, Taga T (2001) DNA methylation is a critical cell-intrinsic determinant of astrocyte differentiation in the fetal brain. Dev Cell 1(6):749–758

    Article  CAS  PubMed  Google Scholar 

  • Tang BL (2009) Neuronal protein trafficking associated with Alzheimer disease: from APP and BACE1 to glutamate receptors. Cell Adhes Migr 3:118–128

    Article  Google Scholar 

  • Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30(4):572–580

    Article  CAS  PubMed  Google Scholar 

  • Trushina NI, Bakota L, Mulkidjanian AY, Brandt R (2019) The evolution of tau phosphorylation and interactions. Front Aging Neurosci 11:256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Turner PR, O’Connor K, Tate WP, Abraham WC (2003) Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory. Prog Neurobiol 70(1):1–32

    Article  CAS  PubMed  Google Scholar 

  • Tyzack GE, Hall CE, Sibley CR, Cymes T et al (2017) A neuroprotective astrocyte state is induced by neuronal signal EphB1 but fails in ALS models. Nat Commun 8(1):1164

    Article  PubMed  PubMed Central  Google Scholar 

  • Ulatowski L, Ghelfi M, West R, Atkinson J, Finno CJ, Manor D (2022) The tocopherol transfer protein TTP mediates Vitamin E trafficking between cerebellar astrocytes and neurons. J Biol Chem 298(3):101712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vahedi G, Takahashi H, Nakayamada S, Sun HW, Sartorelli V, Kanno Y, O’Shea JJ (2012) STATs shape the active enhancer landscape of T cell populations. Cell 151(5):981–993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Varela G, Varona L, Anderson K, Sansoni J (2011) Alzheimer’s care at home: a focus on caregivers strain. Prof Inferm 64(2):113–117

    PubMed  PubMed Central  Google Scholar 

  • Verkhratsky A (2019) Astroglial calcium signaling in aging and Alzheimer’s disease. Cold Spring Harb Perspect Biol 11(7):a035188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vuong B, Hogan-Cann AD, Alano CC, Stevenson M, Chan WY, Anderson CM, Swanson RA, Kauppinen TM (2015) NF-κB transcriptional activation by TNFα requires phospholipase C, extracellular signal-regulated kinase 2 and poly(ADP-ribose) polymerase-1. J Neuroinflammation 12:229

    Article  PubMed  PubMed Central  Google Scholar 

  • Webster B, Hansen L, Adame A, Crews L, Torrance M, Thal L et al (2006) Astroglial activation of extracellular-regulated kinase in early stages of Alzheimer disease. J Neuropathol Exp Neurol 65:142–151

    Article  CAS  PubMed  Google Scholar 

  • Wilkie CM, Barron JC, Brymer KJ, Barnes JR, Nafar F, Parsons MP (2021) The effect of GLT-1 upregulation on extracellular glutamate dynamics. Front Cell Neurosci 15:661412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu Z, Guo Z, Gearing M, Chen G (2014) Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer’s (corrected) disease model. Nat Commun 5:4159

    Article  CAS  PubMed  Google Scholar 

  • Xiao Q, Du Y, Wu W, Yip HK (2010) Bone morphogenetic proteins mediate cellular response and, together with Noggin, regulate astrocyte differentiation after spinal cord injury. Exp Neurol 221(2):353–366

    Article  CAS  PubMed  Google Scholar 

  • Xiu J, Nordberg A, Zhang JT, Guan ZZ (2005) Expression of nicotinic receptors on primary cultures of rat astrocytes and up-regulation of the alpha7, alpha4 and beta2 subunits in response to nanomolar concentrations of the beta-amyloid peptide(1-42). Neurochem Int 47(4):281–290

    Article  CAS  PubMed  Google Scholar 

  • Yao GL, Kato H, Khalil M, Kiryu S, Kiyama H (1997) Selective upregulation of cytokine receptor subchain and their intracellular signalling molecules after peripheral nerve injury. Eur J Neurosci 9:1047–1054

    Article  CAS  PubMed  Google Scholar 

  • Ye B, Shen H, Zhang J, Zhu YG, Ransom BR, Chen XC, Ye ZC (2015) Dual pathways mediate β-amyloid stimulated glutathione release from astrocytes. Glia 63(12):2208–2219

    Article  PubMed  Google Scholar 

  • Yoshizumi M, Eisenach JC, Hayashida K (2012) Riluzole and gabapentinoids activate glutamate transporters to facilitate glutamate-induced glutamate release from cultured astrocytes. Eur J Pharmacol 677(1-3):87–92

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

All the schematic diagrams were made using Biorender.com software.

Conflicts of Interest

The authors have no conflicts of interest to declare that are relevant to the content of this article.

Ethics Approval: Not applicable.

Consent to Participate: Yes.

Consent for Publication: Yes.

Availability of Data and Materials: Not applicable.

Competing Interests: None.

Funding: None.

Authors’ Contributions: All authors contributed to the study conception and design.

Acknowledgements: The authors acknowledge support from the Principal of Poona College of Pharmacy, Pune.

Disclosure of Potential Conflicts of Interest: Not applicable.

Research Involving Human Participants and/or Animals: Not applicable.

Informed Consent: Not applicable.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Pune, Maharashtra, India

    Gadde Shareena

  2. Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA

    Dileep Kumar

  3. Department of Radiological Sciences, Section of Medical Physics, University of Oklahoma, Norman, OK, USA

    Dee Wu

Authors
  1. Gadde Shareena
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dileep Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dee Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA

    Dileep Kumar

  2. Department of Pharmaceutical Chemistry, KIET School of Pharmacy, KIET Group of Institutions, Delhi-NCR, Ghaziabad, Uttar Pradesh, India

    Vaishali M. Patil

  3. Department of Radiological Sciences, Section of Medical Physics, University of Oklahoma, Norman, OK, USA

    Dee Wu

  4. Nuffield Department of Women’s & Reproductive Health, University of Oxford, Oxford, UK

    Nanasaheb Thorat

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Shareena, G., Kumar, D., Wu, D. (2023). Traversing Through the Trajectory of Pathogenic Astrocytes in Alzheimer’s Disease. In: Kumar, D., Patil, V.M., Wu, D., Thorat, N. (eds) Deciphering Drug Targets for Alzheimer’s Disease. Springer, Singapore. https://doi.org/10.1007/978-981-99-2657-2_8

Download citation

Publish with us

Policies and ethics

Search

Navigation