Abstract:A major challenge to our understanding of the molecular mechanisms of Alzheimer’s disease (AD) has been the lack of physiologically relevant in vitro models which capture the precise patient genome, in the cell type of interest, with physiological expression levels of the gene(s) of interest. Induced pluripotent stem cell (iPSC) technology, together with advances in 2D and 3D neuronal differentiation, offers a unique opportunity to overcome this challenge and generate a limitless supply of human neurons for in… Show more
“…Aβ42 direct expression models all exhibit chronic progressive ND. Human iPS AD models appear to be a promising way to experimentally investigate AD mechanisms in a human genetic context [22,58–60] but unfortunately they also fail to progress to ND.…”
Section: Discussionmentioning
confidence: 99%
“…One principal finding of this study is that direct expression of secretory Aβ40 or Aβ42 in cultured human neurons is sufficient to result in a host of AD-like phenotypes up to and including progressive ND. Progressive ND has not been adequately modeled in other non-human animal [6] or current human cellular AD models [22,60] and this phenotypic deficiency has led in part to some of the controversy regarding the role of Aβ in AD [20,63]. The amyloid hypothesis [18] proposes that Aβ is a primary driver for a host of downstream pathogenic cascades terminating in ND.…”
Section: Discussionmentioning
confidence: 99%
“…We used H9 ES cells as the parental genotype in this study since they are widely used in many neuronal differentiation protocols, have been successfully edited and have a SAD associated APOε4/APOε3 genotype [49]. An ongoing challenge in constructing relevant neurodegenerative stem cell models is differentiation to specific cell types involved in the disease [60]. Many types of neurons degenerate in AD and we initially tested a differentiation protocol designed to produce an enrichment of cholinergic basal forebrain-like neurons that was used to generate H9 derived neurons susceptible to Aβ42 oligomers [74].…”
32 We describe construction and phenotypic analysis of a human embryonic stem cell model of 33 progressive A-dependent neurodegeneration (ND) with potential relevance to Alzheimer's 34 disease (AD). We modified one allele of the normal APP locus to directly express a secretory 35 form of A40 or A42, eliminating the need for amyloidogenic APP proteolysis. Following 36 neuronal differentiation edited cell lines specifically accumulate aggregated/oligomeric A, 37 exhibit a synaptic deficit and have an abnormal accumulation of endolysosomal vesicles. Edited 38 cultures progress to a stage of overt ND. All phenotypes appear at earlier culture times for A42 39 relative to A40. Whole transcriptome RNA-Seq analysis identified 23 up and 70 down 40 regulated genes (DEGs) with similar directional fold change but larger absolute values in the 41 A42 samples suggesting common underlying pathogenic mechanisms. Pathway/annotation 42 analysis suggested that down regulation of extracellular matrix and cilia functions are 43 significantly overrepresented. This cellular model could be useful for uncovering mechanisms 44 directly linking A to neuronal death and as a tool to screen for new therapeutic agents that slow 45 or prevent human ND.
Introduction47 Alzheimer's disease (AD) is a chronic progressive neurodegenerative disorder with a decade's 48 long preclinical phase. Clinical features include memory loss accompanied by progressive 49 cognitive dysfunction, cortical atrophy and ultimately death. Neuropathology is well defined by 50 a widespread accumulation of two prominent lesions in cortical brain regions: amyloid plaques 51 and neurofibrillary tangles. Plaques are composed primarily of higher-ordered aggregates of 52 small A peptides derived from amyloidogenic proteolysis of a large transmembrane amyloid 53 precursor protein (APP). Tangles are composed largely of hyperphosphorylated aggregates of a 54 microtubule stabilizing protein tau, a product of the MAPT gene. All forms of AD exhibit 55 accumulation of both A plaques and neurofibrillary tangles and both are considered necessary 56 for a definitive postmortem diagnosis [1]. Both plaque and tangle neuropathology correlate with 57 decrements in cognitive function in AD, but our mechanistic understanding of how these lesions 58 contribute to progressive neurodegeneration (ND) is still incomplete [2]. The reasons for this 59 include the inherent complexity of the disease as well as inadequacies of current animal and 60 cellular experimental models. 61 There are two general forms of AD: a rare autosomal dominant familial form (FAD) and the 62 more prevalent sporadic form (SAD). Both FAD and SAD have a complex genetic component 63 (i.e. >20 identified risk alleles with APOE4 being the most prominent), significant life-style 64 associations (obesity, sleep, exercise, etc.), several associated co-morbidities (i.e. diabetes, head 65 trauma), and of course the most important correlate of all, old age. This complexity coupled with 66 the lengthy time course of the disea...
“…Aβ42 direct expression models all exhibit chronic progressive ND. Human iPS AD models appear to be a promising way to experimentally investigate AD mechanisms in a human genetic context [22,58–60] but unfortunately they also fail to progress to ND.…”
Section: Discussionmentioning
confidence: 99%
“…One principal finding of this study is that direct expression of secretory Aβ40 or Aβ42 in cultured human neurons is sufficient to result in a host of AD-like phenotypes up to and including progressive ND. Progressive ND has not been adequately modeled in other non-human animal [6] or current human cellular AD models [22,60] and this phenotypic deficiency has led in part to some of the controversy regarding the role of Aβ in AD [20,63]. The amyloid hypothesis [18] proposes that Aβ is a primary driver for a host of downstream pathogenic cascades terminating in ND.…”
Section: Discussionmentioning
confidence: 99%
“…We used H9 ES cells as the parental genotype in this study since they are widely used in many neuronal differentiation protocols, have been successfully edited and have a SAD associated APOε4/APOε3 genotype [49]. An ongoing challenge in constructing relevant neurodegenerative stem cell models is differentiation to specific cell types involved in the disease [60]. Many types of neurons degenerate in AD and we initially tested a differentiation protocol designed to produce an enrichment of cholinergic basal forebrain-like neurons that was used to generate H9 derived neurons susceptible to Aβ42 oligomers [74].…”
32 We describe construction and phenotypic analysis of a human embryonic stem cell model of 33 progressive A-dependent neurodegeneration (ND) with potential relevance to Alzheimer's 34 disease (AD). We modified one allele of the normal APP locus to directly express a secretory 35 form of A40 or A42, eliminating the need for amyloidogenic APP proteolysis. Following 36 neuronal differentiation edited cell lines specifically accumulate aggregated/oligomeric A, 37 exhibit a synaptic deficit and have an abnormal accumulation of endolysosomal vesicles. Edited 38 cultures progress to a stage of overt ND. All phenotypes appear at earlier culture times for A42 39 relative to A40. Whole transcriptome RNA-Seq analysis identified 23 up and 70 down 40 regulated genes (DEGs) with similar directional fold change but larger absolute values in the 41 A42 samples suggesting common underlying pathogenic mechanisms. Pathway/annotation 42 analysis suggested that down regulation of extracellular matrix and cilia functions are 43 significantly overrepresented. This cellular model could be useful for uncovering mechanisms 44 directly linking A to neuronal death and as a tool to screen for new therapeutic agents that slow 45 or prevent human ND.
Introduction47 Alzheimer's disease (AD) is a chronic progressive neurodegenerative disorder with a decade's 48 long preclinical phase. Clinical features include memory loss accompanied by progressive 49 cognitive dysfunction, cortical atrophy and ultimately death. Neuropathology is well defined by 50 a widespread accumulation of two prominent lesions in cortical brain regions: amyloid plaques 51 and neurofibrillary tangles. Plaques are composed primarily of higher-ordered aggregates of 52 small A peptides derived from amyloidogenic proteolysis of a large transmembrane amyloid 53 precursor protein (APP). Tangles are composed largely of hyperphosphorylated aggregates of a 54 microtubule stabilizing protein tau, a product of the MAPT gene. All forms of AD exhibit 55 accumulation of both A plaques and neurofibrillary tangles and both are considered necessary 56 for a definitive postmortem diagnosis [1]. Both plaque and tangle neuropathology correlate with 57 decrements in cognitive function in AD, but our mechanistic understanding of how these lesions 58 contribute to progressive neurodegeneration (ND) is still incomplete [2]. The reasons for this 59 include the inherent complexity of the disease as well as inadequacies of current animal and 60 cellular experimental models. 61 There are two general forms of AD: a rare autosomal dominant familial form (FAD) and the 62 more prevalent sporadic form (SAD). Both FAD and SAD have a complex genetic component 63 (i.e. >20 identified risk alleles with APOE4 being the most prominent), significant life-style 64 associations (obesity, sleep, exercise, etc.), several associated co-morbidities (i.e. diabetes, head 65 trauma), and of course the most important correlate of all, old age. This complexity coupled with 66 the lengthy time course of the disea...
“…Furthermore, to date, there are no data that clearly presents the advantages of using human skin fibroblasts for translational drug discovery where outcomes are confirmed in in vivo models. The demonstration that fibroblasts could be directly used to design individualized treatment for the central nervous system disorders could offer relatively inexpensive tool that may significantly reduce the high cost of alternative approaches (e.g., iPSC‐derived neuronal cells or multiple animal models) [87]. Nevertheless, high translational potential of outcomes generated in peripheral cells for a development of biomarkers and targeted therapeutics, the opportunity to conduct extensive evaluations using systems biology approaches to determine mechanisms and complex functional connections in the context of the individuals' genetic and epigenetic makeup, the ability to collect peripheral cells longitudinally from the same individuals, and relatively low cost associated with the utilization of human cells could provide complementary or even primary tools for AD research and clinical applications.…”
Section: Major Challenges To the Hypothesis And Future Experimentsmentioning
Introduction
Development of efficacious therapeutic interventions for Alzheimer's disease (AD) is hampered by the lack of understanding early disease mechanisms, biomarkers, and models that mimic complex pathophysiology of human disease.
Methods
This article aims to assess to what extent peripheral cells recapitulate molecular mechanisms altered in the brain and could be used as translational models for the development of individualized medicine for AD.
Results
Multiple studies suggest that AD is a systemic disorder with an active crosstalk between brain and periphery where multiple pathways altered in the brain cells are also affected in plasma, cerebrospinal fluid, and other peripheral cells of AD patients.
Discussion
Additional studies to validate molecular mechanisms in peripheral cells using advanced system biology techniques and well‐characterized cohorts of AD patients together with the development of standardized protocols should be considered to support the application of peripheral cells in AD research.
“…In addition to rodent models, recent advances in stem cell technologies have promoted the use of human-based cell models for AD research. For example, it is now possible to model AD in vitro by using induced pluripotent stem cells (iPSCs) and cells derived from these by differentiation [53][54][55].…”
Section: Astrocytes In Alzheimer's Diseasementioning
The brain is one of the most energy-requiring organs in the human body. Mitochondria not only generate this energy, but are centrally involved critical cellular functions including maintenance of calcium homeostasis, synthesis of biomolecules, and cell signaling. Even though neurons and astrocytes preferentially use different energy substrates and metabolic pathways, these two cell types are intricately linked in their energy metabolism. Recently it has become clear that astrocytes have a key role in the regulation and support of the neuronal mitochondrial quality control, yet several questions remain unanswered to fully understand the mechanisms of mitochondrial function, transport, turnover and degradation in astrocytes. Alzheimer's disease is the most common neurodegenerative disorder, the exact mechanisms of which remain incompletely understood. The fact that astrocytic mitochondrial dysfunction is an early event in the pathogenesis of Alzheimer's disease suggests that more research on mitochondrial function and impairment is required in the hopes of disease alleviation in the future.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
