Abstract
The pathological potential of human astroglia in Alzheimer's disease (AD) was analysed in vitro using induced pluripotent stem cell (iPSC) technology. Here, we report development of a human iPSC-derived astrocyte model created from healthy individuals and patients with either early-onset familial AD (FAD) or the late-onset sporadic form of AD (SAD). Our chemically defined and highly efficient model provides >95% homogeneous populations of human astrocytes within 30 days of differentiation from cortical neural progenitor cells (NPCs). All astrocytes expressed functional markers including glial fibrillary acidic protein (GFAP), excitatory amino acid transporter-1 (EAAT1), S100B and glutamine synthetase (GS) comparable to that of adult astrocytes in vivo. However, induced astrocytes derived from both SAD and FAD patients exhibit a pronounced pathological phenotype, with a significantly less complex morphological appearance, overall atrophic profiles and abnormal localisation of key functional astroglial markers. Furthermore, NPCs derived from identical patients did not show any differences, therefore, validating that remodelled astroglia are not as a result of defective neural intermediates. This work not only presents a novel model to study the mechanisms of human astrocytes in vitro, but also provides an ideal platform for further interrogation of early astroglial cell autonomous events in AD and the possibility of identification of novel therapeutic targets for the treatment of AD.
Highlights
All diseases, including neurological disorders, can be broadly defined as homeostatic failures within tissues, organs or systems
We show that cortical neurones derived from identical familial AD (FAD) and sporadic (late-onset) form of AD (SAD) patients exhibit elevated pathological Aβ-42 secretion and hyperphosphorylated tau species compared with healthy individuals, validating an Alzheimer’s disease (AD) phenotype in these cells
The results presented reveal that both SAD and FAD neural progenitor cells (NPCs) retain their characteristic morphology, expression of canonical markers and are able to generate mature cortical neurones with the same efficiency as healthy derived NPCs, Importantly, any changes in astroglia are not as a result of defective neuronal intermediates
Summary
All diseases, including neurological disorders, can be broadly defined as homeostatic failures within tissues, organs or systems. Astrocytes are fundamental for synaptogenesis and synaptic maintenance; they control ion homeostasis in the CNS interstitium and are indispensable for turnover of major neurotransmitters, such as glutamate, GABA and adenosine.[1,2] In addition, astroglial cells are endowed with an evolutionary conserved defensive programme known as reactive gliosis, which develops in response to CNS lesions and is manifested by a spectrum of disease-specific cellular responses including hypertrophy and upregulation of intermediate filaments.[3,4] Astrocytopathy is a central element of neurological disorders and, depending on the disease context, astrocytes undergo complex changes, which vary from astroglial atrophy with loss of function, to pathological remodelling or reactivity and may develop alone or in combination.[5,6,7,8] In Alzheimer’s disease (AD) animal models, atrophic astrocytes have been detected at the earliest stages of the disease, with hypertrophic reactive astrocytes appearing later in disease progression, in response to their proximity to extracellular accumulations of β-amyloid (Aβ).[9,10,11,12] signs of astroglial reactivity and atrophy were detected in AD patients by positron emission tomography using 11C-deteriumL-deprenyl.[13] These observations led to a hypothesis of glial paralysis being a fundamental factor in evolution of AD.[14]. We did not observe any differences in early neuronal commitment in early AD-derived neurones compared with healthy controls, indicating the cell autonomous pathological potential of astroglia and further confirming that cellular pathology does not stem from defective neural progenitors
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