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• W2795890990 abstract "Neurono-centric doctrine, which regards neurones as the main and the only substrate of pathological evolution, lies at the very core of philosophy of neurology; the neurono-centricity defines, to a very large extend, the therapeutic strategies and searches for new pharmacological treatments. Pathological responses of the neuroglia are commonly thought to be secondary, which is highlighted in the concept of glial reactivity that is universally considered as a generalized and non-specific cellular riposte to any form of an insult to the nervous system. The pathological potential of neuroglia is, however, much more complex and multifaceted, and the paper by Matjaz Stenovec, Robert Zorec and their collaborators1 published in this issue of Acta Physiologica studies the cellular pathology of astrocytes in the context of Alzheimer's disease (AD). The fundamental role of glia in pathology was forestalled by the author of the concept of neuroglia Rudolph Virchow, who considered glia as “one of the most frequent seats of morbid change”.2 Pathological remodelling of glial cells has been frequently and comprehensively described in late 19th and early 20th century; the most prominent neuroanatomists and neuropathologists of those days (Santiago Ramon y Cajal, Franz Nissl, Carl Frommann, Ludwig Merzbacher, Alois Alzheimer, Nicolas Achucarro and Pio del Rio Hortega to name a few) provided detailed analysis of pathological metamorphosis and pathological role of glial cells.3 The contribution of glia to neurological disorders regained interest in the last decade, when numerous complex and distinct glial pathological changes have been discovered. Astrocytes (one of the main types of glia in the central nervous system (CNS), the other three being oligodendrocytes, NG2 glia and microglia) provide for homoeostasis and defence of the brain and the spinal cord.4 Astrocytes control CNS homoeostasis at all levels of organization from molecular to organ; astrocytes influence excitability of the nervous tissue through regulating ion content of the interstitial fluids (iconostasis), they form the gliocrine secretory system that releases a variety of signalling and trophic molecules indispensable for shaping neuronal networks and effect synaptic transmission through uptake and catabolism of neurotransmitters and supply of neurotransmitter's precursors.4 Astrocytes provide an active defence to the brain by mounting astrogliotic response to various types of brain lesions; this astrogliotic remodelling, however, is not an all-or-none event, but rather a continuum of biochemical, morphological and physiological changes resulting in multiple context and disease-specific phenotypes.5-7 Numerous experiments also demonstrated that inhibition of astrogliosis often exacerbates neuropathology.5 Astrogliosis, however, can be maladaptive and assume neurotoxic phenotypes in conditions of severe or chronic pathology.8 Neuropathological role of astroglia is not limited to reactivity, but also includes distinct pathological changes summarily known as astrocytopathies.5, 7, 9 These include astrodegeneration, which results in astroglial atrophy and loss of function and pathological remodelling of astrocytes. Astroglial atrophy with loss of function was identified in a surprisingly wide range of diseases from toxic encephalopathies, to neuropsychiatric conditions, addictive disorders and neurodegeneration. Loss of astroglial ability to contain extracellular glutamate, for example, underlies excitotoxic neuronal death in Wernicke encephalopathy, in neurological deficits caused by heavy metals poisoning or in amyotrophic lateral sclerosis.5, 7 Astroglial atrophy with loss of astrocytes is well documented in schizophrenia and major depressive disorders and is also manifest in neurodegeneration.5, 7 Astroglial pathological remodelling is highlighted in Alexander disease, when astrocytes carry mutated genes encoding glial fibrillary acidic protein, ensuing changes in astroglia, in yet unknown way, result in severe deficits in the white matter.10 Despite all these observations and conceptual shift in cellular neuropathology, the fundamental question of whether astroglial changes reflect cell-autonomous mechanisms remains unresolved. The notable exception of course is Alexander disease, because neurones do not express GFAP and hence the pathology is clearly associated with primary astroglial lesion. The article of Stenovec et al1 focuses specifically on astrocytes in the context of AD. Astrogliopathology in AD is complex, is region specific and is changing in different disease stages. Experiments on genetic animal models (which reproduce only certain aspects of family AD) found astroglial atrophy in early AD with particular prevalence in the entorhinal and prefrontal cortices; this atrophy was complemented with astroglial reactivity after the emergence of senile plaques.11 Astroglial reactivity was also detected in humans by deprenyl-based positron emission brain tomography; this reactivity was depressed at the late stages of the disease that was clinically characterized by a transition from mild cognitive impairment to severe dementia.11 All in all failure in astroglial homoeostatic capacity in combination with compromised astroglial reactivity seem to contribute (if not to define) the progression of AD. To address the cell-autonomous astroglial pathology associated with AD, Stenovec et al imaged astrocytes using high-resolution confocal microscopy. First12 they analysed vesicular motility in parallel with Ca2+ signalling in astrocytes isolated from 3 × TG AD mice (in this animal model mice harbour three human-mutated genes associated with AD—genes encoding amyloid precursor protein, presenilin-1 and tau). This study revealed suppressed vesicular motility and aberrant Ca2+ signalling in astrocytes isolated from the AD environment. These findings were suggestive of cell-autonomous astroglial pathology, and yet the cells in question were exposed for AD brain environment for a long while and hence the changes observed could have reflected some adaptive response. To clarify this matter further, Stenovec et al1 transfected healthy rat astroglial cells with a specific presenilin-1 mutated gene PS1ΔE9 linked to AD. To monitor vesicular motility, they cotransfected astrocytes with fluorescent protein-tagged atrial natriuretic peptide (which is stored in astroglial secretory organelles) or with vesicular glutamate transporter 1, which is present in a subset of astroglial vesicles. Subsequently, the authors followed the vesicles in living cells. The experiments demonstrated substantial reduction in vesicular trafficking in as well as suppression of atrial natriuretic peptide release from astrocytes expressing AD-related presenilin-1 gene. These experiments clearly demonstrated that astrocytes exhibit cell-autonomous pathological signature caused by the expression of mutated gene associated with AD. Changes in vesicular dynamics affect not only secretory properties of astrocytes but reflect deficient vesicular trafficking network, which in turn may affect astroglial plasticity and morphology, being possibly related to astroglial atrophy.13 However, encouraging these results are we face another major challenge: How do astrocytes change in sporadic AD? This latter form occurs only in humans, accounts for an absolute majority (~99%) of clinical pathology and cannot be reproduced in animals. In addition, human astrocytes differ fundamentally from astrocytes of rodents in their size, complexity and specific forms.14 In consequence experiments on AD-affected human, astrocytes are to be conceived. How human astroglia can be experimentally interrogated? Do astrocytes derived from pluripotent stem cells obtained from peripheral tissues of patients with AD15 keep pathological phenotype? Can non-invasive imaging techniques visualize astroglia in the in vivo human brain? These are imperative questions that have to be addressed to advance our knowledge of the disease, of the underlying cellular pathophysiology and of the new therapeutic strategies desperately needed to contain the pandemic explosion of age-dependent neurodegenerative disorders. The authors declare no conflict of interest." @default.
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• W2795890990 date "2018-04-19" @default.
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• W2795890990 title "Cell-autonomous astrocytopathy in Alzheimer's disease" @default.
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• W2795890990 doi "https://doi.org/10.1111/apha.13070" @default.
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