The Cellular Phase of Alzheimer’s Disease

Strooper, Bart De; Karran, Eric

doi:10.1016/j.cell.2015.12.056

Cited by 1,439 publications

(1,331 citation statements)

References 103 publications

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“…Glial and neuroimmune mechanisms have been extensively characterized in the context of pathological pain (Grace et al, 2014a), while researchers attempting to decode the complex etiology of neurodegenerative disorders such as Alzheimer's disease have also argued for a more holistic framework, where the interactions and compensatory responses between neurons, glia, and vascular cells all contribute to the progression of the disease (De Strooper and Karran, 2016). Given their role in immune surveillance and debris clearance, it is perhaps unsurprising that microglial activation in particular has been implicated in neurodegenerative diseases beyond Alzheimer's disease, including multiple sclerosis and Parkinson's disease (Chung et al, 2015b;Heneka et al, 2015;Hong et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

Lacagnina

Rivera

Bilbo

2016

Neuropsychopharmacol

218

170

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Drugs of abuse cause persistent alterations in synaptic plasticity that may underlie addiction behaviors. Evidence suggests glial cells have an essential and underappreciated role in the development and maintenance of drug abuse by influencing neuronal and synaptic functions in multifaceted ways. Microglia and astrocytes perform critical functions in synapse formation and refinement in the developing brain, and there is growing evidence that disruptions in glial function may be implicated in numerous neurological disorders throughout the lifespan. Linking evidence of function in health and under pathological conditions, this review will outline the glial and neuroimmune mechanisms that may contribute to drug-abuse liability, exploring evidence from opioids, alcohol, and psychostimulants. Drugs of abuse can activate microglia and astrocytes through signaling at innate immune receptors, which in turn influence neuronal function not only through secretion of soluble factors (eg, cytokines and chemokines) but also potentially through direct remodeling of the synapses. In sum, this review will argue that neural-glial interactions represent an important avenue for advancing our understanding of substance abuse disorders.

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Section: Resultsmentioning

confidence: 99%

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

Lacagnina

Rivera

Bilbo

2016

Neuropsychopharmacol

218

170

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“…Complement‐activated oligodendrocytes are found in various neurodegenerative conditions including AD (Yamada, Akiyama, & McGeer, 1990). Overall, oligodendrocytes, although constituting ~75% of the neuroglia cells in the neocortex, are treated as a silent majority in AD research (De Strooper & Karran, 2016). …”

Section: Cellular Changes In Aging and Admentioning

confidence: 99%

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

et al. 2018

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Alzheimer's disease is the most prevalent cause of dementia, which is defined by the combined presence of amyloid and tau, but researchers are gradually moving away from the simple assumption of linear causality proposed by the original amyloid hypothesis. Aging is the main risk factor for Alzheimer's disease that cannot be explained by amyloid hypothesis. To evaluate how aging and Alzheimer's disease are intrinsically interwoven with each other, we review and summarize evidence from molecular, cellular, and system level. In particular, we focus on study designs, treatments, or interventions in Alzheimer's disease that could also be insightful in aging and vice versa.

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“…In addition to amyloid plaques and neurofibrillary tangles, the two signature pathological lesions, Alzheimer's brains manifest prominent astrocytic and microglial reactions (De Strooper & Karran, 2016; Heneka et al, 2015; Osborn, Kamphuis, Wadman, & Hol, 2016; Serrano‐Pozo, Muzikansky, et al, 2013; Verkhratsky, Parpura, Pekna, Pekny, & Sofroniew, 2014). Glia‐mediated neuroinflammation has been proposed as a potential mechanism underlying AD pathogenesis and over the past decade activated microglia have been the focus of increasing research (Heneka et al, 2015; Heppner, Ransohoff, & Becher, 2015); however, the precise contribution of reactive astrocytes is still undetermined.…”

Section: Introductionmentioning

confidence: 99%

Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer's disease

Gómez-Arboledas

Dávila

Sánchez-Mejías

et al. 2017

Glia

161

126

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Reactive astrogliosis, a complex process characterized by cell hypertrophy and upregulation of components of intermediate filaments, is a common feature in brains of Alzheimer's patients. Reactive astrocytes are found in close association with neuritic plaques; however, the precise role of these glial cells in disease pathogenesis is unknown. In this study, using immunohistochemical techniques and light and electron microscopy, we report that plaque‐associated reactive astrocytes enwrap, engulf and may digest presynaptic dystrophies in the hippocampus of amyloid precursor protein/presenilin‐1 (APP/PS1) mice. Microglia, the brain phagocytic population, was apparently not engaged in this clearance. Phagocytic reactive astrocytes were present in 35% and 67% of amyloid plaques at 6 and 12 months of age, respectively. The proportion of engulfed dystrophic neurites was low, around 7% of total dystrophies around plaques at both ages. This fact, along with the accumulation of dystrophic neurites during disease course, suggests that the efficiency of the astrocyte phagocytic process might be limited or impaired. Reactive astrocytes surrounding and engulfing dystrophic neurites were also detected in the hippocampus of Alzheimer's patients by confocal and ultrastructural analysis. We posit that the phagocytic activity of reactive astrocytes might contribute to clear dysfunctional synapses or synaptic debris, thereby restoring impaired neural circuits and reducing the inflammatory impact of damaged neuronal parts and/or limiting the amyloid pathology. Therefore, potentiation of the phagocytic properties of reactive astrocytes may represent a potential therapy in Alzheimer's disease.

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The Cellular Phase of Alzheimer’s Disease

Cited by 1,439 publications

References 103 publications

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer's disease

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