The University of Manchester Research Astroglial atrophy in Alzheimer’s disease DOI: 10.1007/s00424-019-02310-2 Document Version Accepted author manuscript Link to publication record in Manchester Research Explorer Citation for published version (APA): Verkhratsky, A., Rodrigues, J. J., Pivoriunas, A., Zorec, R., & Semyanov, A. (2019). Astroglial atrophy in Alzheimer’s disease. Pflugers Archiv European Journal of Physiology, 471(10), 1247-1261. https://doi.org/10.1007/s00424-019-02310-2 Published in: Pflugers Archiv European Journal of Physiology Citing this paper Please note that where the full-text provided on Manchester Research Explorer is the Author Accepted Manuscript or Proof version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version. 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Oct. 2021 1 1 2 Astroglial atrophy in disease 3 4 5 6 Alexei Verkhratsky1,2, Jose Julio Rodrigues3,4, Augustas Pivoriunas5, Robert Zorec6,7 & 7 8,9 8 Alexey Semyanov 9 10 1Faculty of Biology, Medicine and Health, The University of Manchester, 11 Manchester, M13 9PT, UK; 12 2 13 Achucarro Center for Neuroscience, IKERBASQUE, Basque Foundation for 14 Science, 48011 Bilbao, Spain; 15 3BioCruces Health Research Institute, IKERBASQUE, Basque Foundation for 16 Science 48011 Bilbao, Spain; 17 4 18 Department of Neuroscience, The University of the Basque Country UPV/EHU, 19 Plaza de Cruces 12, 48903, Barakaldo, Bizkaia, Spain; 20 5Department of Stem Cell Biology, State Research Institute Centre for Innovative 21 Medicine, -08406 Vilnius, Lithuania; 22 6University of Ljubljana, Medical Faculty, Institute of Pathophysiology, Laboratory of 23 24 Neuroendocrinology and Molecular Cell Physiology, Zaloska cesta 4; SI-1000, 25 Ljubljana, Slovenia; 26 7Celica, BIOMEDICAL, Technology Park 24, 1000 Ljubljana, Slovenia; 27 8Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of 28 Sciences, Miklukho-Maklaya street 16/10, Moscow, 117997, Russia; 29 9 30 Sechenov First Moscow State Medical University, Moscow, Russia 31 32 33 Send all correspondence to: 34 35 Alexei Verkhratsky 36 The University of Manchester, 37 Oxford Road, 38 Manchester, M13 9PT, UK, 39 Telephone +44 (0)161-2757324, 40 41 e-mail: [email protected] 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 Abstract 1 2 Astrocytes, a class of morphologically and functionally diverse primary homeostatic 3 4 neuroglia, are key keepers of neural tissue homeostasis and fundamental contributors 5 to brain defence in pathological contexts. Failure of astroglial support and defence 6 facilitate the evolution of neurological diseases, which often results in aberrant 7 synaptic transmission, neurodegeneration, and death of neurones. 8 disease (AD) astrocytes undergo complex and multifaceted metamorphoses ranging 9 10 from atrophy with loss of function to reactive astrogliosis with hypertrophy. 11 Astroglial asthenia underlies reduced homeostatic support and neuroprotection that 12 may account for impaired synaptic transmission and neuronal demise. Reactive 13 astrogliosis which mainly develops in astrocytes associated with senile plaque is 14 15 prominent at the early to moderate stages of AD manifested by mild cognitive 16 impairment; down-regulation of astrogliosis (reflecting astroglial paralysis) is 17 associated with late stages of the disease characterised by severe dementia. Cell- 18 specific therapies aimed at boosting astroglial supportive and defensive capabilities 19 and preventing astroglial paralysis may offer new directions in preventing, arresting 20 21 or even curing AD-linked neurodegeneration. 22 23 Keywords: Astrocytes; Astroglial atrophy; Astrogliosis; 24 Neurological diseases; Neurodegeneration 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 The epidemic of neurodegenerative diseases 1 2 Robert Katzman in 1976 3 4 [63] spreads through the aging world population with little prospective for therapeutic 5 containment. Despite remarkable progress in understanding the biochemistry and 6 genetics of neurodegenerative processes the genesis and evolution of the majority of 7 sporadic cases remain obscure, whereas pharmacological options remain symptomatic 8 [122]. The ultimate outcome of neurodegeneration is neural cell death, brain atrophy 9 10 and loss of brain function. A direct link between the decrease in the size (i.e., atrophy) 11 of the brain tissue and decrease in cognitive capabilities (i.e., dementia) was 12 suggested by Thomas de Willis at the end of 17th century [156]. Aberrant processing 13 of proteins lies at the core of neurodegeneration; compromised synthesis/degradation 14 15 or clearance of proteins results in accumulation of intra- 16 proteins [55,118]. Despite the multitude of specific pathological pathways 17 idiosyncratic for certain disease (e.g. -amyloid accumulation and abnormal tau 18 phosphorylation in Alzheim (AD), -synuclein accumulation in 19 20 21 disease) all neurodegenerative processes share a common pathological phenotype - 22 they all trigger cell death and destroy connectivity in the neural networks. 23 24 Extracellular depositions of -amyloid and intracellular accumulation of 25 26 misphosphorylated tau protein (both processes are, most likely, interrelated with 27 indications for tau pathology being driven by -amyloid accumulation) are common 28 histological denominators of the AD brains. Occurrence of these lesions, however, 29 varies and there is no obvious correlation between their densities and the severity of 30 31 dementia. The concept that tissue depositions of pathological material are causative 32 for neurodegeneration was proposed by Oskar Fischer in 1907 [39,40]. The specific 33 role for -amyloid in the AD (the amyloid cascade hypothesis), remains, however, 34 disputed [61,87,23]. Amyloid plaques occur in several neurological diseases; they 35 36 were initially discovered by Paul Blocq and Gheorghe Marinescu in post-mortem 37 brains from elderly patients with chronic epilepsy [11]; amyloid depositions populate 38 posttraumatic nervous tissues, tissues infected with prions and brains affected by 39 pathology is characteristic of 40 fronto-temporal dementia and prion infection. In recent years the new concept of tau 41 42 astrogliopathy had emerged, after the discovery of multiple pathological phenotypes 43 of astrocytes infested with tau and related to specific forms of age-associated 44 dementia [71]. Even acute sleep deprivation for a single night causes accumulation of 45 -amyloid, which is seemingly unrelated to any predisposition to AD [125]. 46 47 48 It is, however, almost beyond dispute that the gross histopathological signs of AD 49 became apparent at the late stages of the disease. The AD begins with prolonged (10 - 50 15 years) asymptomatic phase, when the overall cognitive function remains (almost) 51 52 intact, although pathological changes begin to accumulate. It is most probable that 53 from the very beginning AD-pathology affects synaptic transmission. There is a close 54 correlation between synaptic alterations and cognitive impairments in AD patients, 55 and these synaptic alterations are often considered to occur at the very early (pre- 56 plaque) stages of the disease [31,135,55,89]. Nervous tissue, affected by AD is 57 58 characterised by compromised synaptic connectivity and neuronal hyperexcitability, 59 which are indicative of dyshomeostasis of ions and neurotransmitters [64,84,42,19]. 60 The brain unwiring in AD is also manifested in white matter damage, which is 61 62 63 64 65 4 observed from the early stages and correlates with cognitive deficit [14]. Finally, the 1 AD alters metabolic homeostasis of the nervous system; region-specific 2 hypometabolism underlies AD-specific diagnostic phenotype used for FDG-PET 3 4 diagnostics [59]. All these features indicate that AD (similarly to other 5 neurodegenerative diseases) is a chronic homeostatic failure of the brain tissue, 6 which, naturally, has to be associated with the failure of the homeostatic neuroglia. 7 8 Astrocytes provide homeostatic support and neuroprotection 9 10 11 The human brain evolved for over ~500 million years from the diffuse nervous 12 system that appeared in the most primitive multicellular organisms. Evolution of 13 nervous system progressed through an increase in the complexity of nervous tissue 14 15 with a parallel increase in heterogeneity and specialisation of neural cells. Emergence 16 of the central nervous system (CNS) with intricate synaptic web required 17 sophisticated homeostatic support and thus much specialisation has occurred among 18 neural cells, which were fundamentally divided into neurones, representing the 19 executive arm and neuroglia, representing the housekeeping branch [111,143]. This 20 21 division of responsibilities reflected the perfection of fast neuronal signalling