scholarly journals Relative Contribution of Amyloid-β Plaque Associated and Plaque Distant Microglia to Alzheimer’S Disease (AD) Progression

2021 ◽  
Author(s):  
Anne-Laure Hemonnot-Girard ◽  
Cédric Meersseman ◽  
Manuela Pastore ◽  
Nathalie Linck ◽  
Catherine Rey ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Spatial Information ◽  
Amyloid Β ◽  
Functional Roles ◽  
Functional Changes ◽  
Relative Contribution ◽  
Negative Impacts ◽  
Opposing Effects ◽  
Transcriptomic Changes

Abstract Background: Research in recent years firmly established that microglial cells play an important role in the pathogenesis of Alzheimer's disease (AD). In parallel, a series of studies showed that, under both homeostatic and pathological conditions, microglia are a heterogeneous cell population. In AD, amyloid-b (Ab) plaque-associated microglia (PAM) display a clearly distinct phenotype compared to plaque-distant microglia (PCM), suggesting that these two microglia subtypes likely differently contribute to disease progression. So far, molecular characterization of PAM was performed indirectly using scRNA-seq approaches or based on markers that are supposedly up-regulated in this microglia subpopulation.Methods: In this study, we combined cell-specific laser capture and RNA-seq analysis to investigate, without preconceived notions of the molecular and/or functional changes that would affect these cells, the functional role of both plaque-associated and plaque-distant microglia. Results: First, we established that this approach allows selective isolation of microglia, while preserving spatial information and preventing transcriptome changes induced by classical purification approaches. Then, we identified, in PAM and PCM subpopulations, networks of co-deregulated genes and analyzed their potential functional roles in AD. Finally, we investigated the dynamics of microglia transcriptomic remodeling at early, intermediate and late stages of the disease. Conclusions: Our comprehensive study demonstrates that the proximity of microglia to Ab-plaques dramatically alters the microglial transcriptome and reveals that these changes can have both positive and negative impacts on the surrounding cells. These opposing effects may be driven by local microglia heterogeneity also demonstrated by this study. Our results also suggest that Ab plaque-associated microglia undergo exhaustion in the later stage of the disease. Our approach leads to molecularly define the overlooked plaque-distant microglia. We show that plaque-distant microglia are not bystanders of the disease, although the transcriptomic changes are far less striking compared to what is observed in plaque-associated microglia. In particular, our results suggest they are involved in Ab oligomer detection and in Ab-plaque initiation, with increased contribution as the disease progresses.

scholarly journals Relative Contribution of Amyloid-β Plaque Associated And Plaque Distant Microglia To Alzheimer’s Disease (AD) Progression

2021 ◽  
Author(s):  
Anne-Laure Hemonnot-Girard ◽  
Cédric Meersseman ◽  
Manuela Pastore ◽  
Nathalie Linck ◽  
Catherine Rey ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Spatial Information ◽  
Amyloid Β ◽  
Functional Roles ◽  
Relative Contribution ◽  
Negative Impacts ◽  
Opposing Effects ◽  
Transcriptomic Changes

Abstract Background: Research in recent years firmly established that microglial cells play an important role in the pathogenesis of Alzheimer's disease (AD). In parallel, a series of studies showed that, under both homeostatic and pathological conditions, microglia are a heterogeneous cell population. In AD, amyloid-b (Ab) plaque-associated microglia (PAM) display a clearly distinct phenotype compared to plaque-distant microglia (PCM), suggesting that these two microglia subtypes likely differently contribute to disease progression. Methods: In this study, we combined cell-specific laser capture and RNA-seq analysis to investigate the functional role of both plaque-associated and plaque-distant microglia. Results: First, we established that this approach allows selective isolation of microglia, while preserving spatial information and preventing transcriptome changes induced by classical purification approaches. Then, we identified, in both microglia subpopulations, networks of co-deregulated genes and analyzed their potential functional roles in AD. In addition, we investigated the dynamics of microglia transcriptomic remodeling at early, intermediate and late stages of the disease. Conclusions: Our comprehensive study demonstrates that the proximity of microglia to Ab-plaques dramatically alters the microglial transcriptome and reveals that these changes can have both positive and negative impacts on the surrounding cells. These opposing effects may be driven by local microglia heterogeneity also demonstrated by this study. Our results also suggest that Ab plaque-associated microglia undergo exhaustion in the later stage of the disease. Our approach also allowed to molecularly define the overlooked plaque-distant microglia. We show, that although the transcriptomic changes are far less striking compared to what is observed in plaque-associated microglia, plaque-distant microglia are not bystanders of the disease. In particular, our results suggest they are involved in Ab oligomer detection and in Ab-plaque initiation, with increased contribution as the disease progresses.

scholarly journals Astrocytes and neuroinflammation in Alzheimer's disease

2014 ◽  
Vol 42 (5) ◽  
pp. 1321-1325 ◽  
Author(s):  
Emma C. Phillips ◽  
Cara L. Croft ◽  
Ksenia Kurbatskaya ◽  
Michael J. O’Neill ◽  
Michael L. Hutton ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inflammatory Responses ◽  
Amyloid Β ◽  
Synaptic Dysfunction ◽  
Amyloid Β Peptide ◽  
Substantial Evidence ◽  
Models Of Disease ◽  
Opposing Effects

Increased production of amyloid β-peptide (Aβ) and altered processing of tau in Alzheimer's disease (AD) are associated with synaptic dysfunction, neuronal death and cognitive and behavioural deficits. Neuroinflammation is also a prominent feature of AD brain and considerable evidence indicates that inflammatory events play a significant role in modulating the progression of AD. The role of microglia in AD inflammation has long been acknowledged. Substantial evidence now demonstrates that astrocyte-mediated inflammatory responses also influence pathology development, synapse health and neurodegeneration in AD. Several anti-inflammatory therapies targeting astrocytes show significant benefit in models of disease, particularly with respect to tau-associated neurodegeneration. However, the effectiveness of these approaches is complex, since modulating inflammatory pathways often has opposing effects on the development of tau and amyloid pathology, and is dependent on the precise phenotype and activities of astrocytes in different cellular environments. An increased understanding of interactions between astrocytes and neurons under different conditions is required for the development of safe and effective astrocyte-based therapies for AD and related neurodegenerative diseases.

scholarly journals Astrocytes and Adenosine A2A Receptors: Active Players in Alzheimer’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Cátia R. Lopes ◽  
Rodrigo A. Cunha ◽  
Paula Agostinho
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
The Elderly ◽  
Synaptic Function ◽  
Morphological Alterations ◽  
Functional Changes ◽  
A2a Receptors ◽  
Novel Therapeutic Strategies

Astrocytes, through their numerous processes, establish a bidirectional communication with neurons that is crucial to regulate synaptic plasticity, the purported neurophysiological basis of memory. This evidence contributed to change the classic “neurocentric” view of Alzheimer’s disease (AD), being astrocytes increasingly considered a key player in this neurodegenerative disease. AD, the most common form of dementia in the elderly, is characterized by a deterioration of memory and of other cognitive functions. Although, early cognitive deficits have been associated with synaptic loss and dysfunction caused by amyloid-β peptides (Aβ), accumulating evidences support a role of astrocytes in AD. Astrocyte atrophy and reactivity occurring at early and later stages of AD, respectively, involve morphological alterations that translate into functional changes. However, the main signals responsible for astrocytic alterations in AD and their impact on synaptic function remain to be defined. One possible candidate is adenosine, which can be formed upon extracellular catabolism of ATP released by astrocytes. Adenosine can act as a homeostatic modulator and also as a neuromodulator at the synaptic level, through the activation of adenosine receptors, mainly of A1R and A2AR subtypes. These receptors are also present in astrocytes, being particularly relevant in pathological conditions, to control the morphofunctional responses of astrocytes. Here, we will focus on the role of A2AR, since they are particularly associated with neurodegeneration and also with memory processes. Furthermore, A2AR levels are increased in the AD brain, namely in astrocytes where they can control key astrocytic functions. Thus, unveiling the role of A2AR in astrocytes function might shed light on novel therapeutic strategies for AD.

scholarly journals Replacement of brain-resident myeloid cells does not alter cerebral amyloid-β deposition in mouse models of Alzheimer’s disease

2015 ◽  
Vol 212 (11) ◽  
pp. 1803-1809 ◽  
Author(s):  
Nicholas H. Varvel ◽  
Stefan A. Grathwohl ◽  
Karoline Degenhardt ◽  
Claudia Resch ◽  
Andrea Bosch ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Myeloid Cells ◽  
Amyloid Β ◽  
Myeloid Cell ◽  
Functional Roles ◽  
Amyloid Load

Immune cells of myeloid lineage are encountered in the Alzheimer’s disease (AD) brain, where they cluster around amyloid-β plaques. However, assigning functional roles to myeloid cell subtypes has been problematic, and the potential for peripheral myeloid cells to alleviate AD pathology remains unclear. Therefore, we asked whether replacement of brain-resident myeloid cells with peripheral monocytes alters amyloid deposition in two mouse models of cerebral β-amyloidosis (APP23 and APPPS1). Interestingly, early after repopulation, infiltrating monocytes neither clustered around plaques nor showed Trem2 expression. However, with increasing time in the brain, infiltrating monocytes became plaque associated and also Trem2 positive. Strikingly, however, monocyte repopulation for up to 6 mo did not modify amyloid load in either model, independent of the stage of pathology at the time of repopulation. Our results argue against a long-term role of peripheral monocytes that is sufficiently distinct from microglial function to modify cerebral β-amyloidosis. Therefore, myeloid replacement by itself is not likely to be effective as a therapeutic approach for AD.

scholarly journals Cholesterol Dysmetabolism in Alzheimer’s Disease: A Starring Role for Astrocytes?

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1890
Author(s):  
Erica Staurenghi ◽  
Serena Giannelli ◽  
Gabriella Testa ◽  
Barbara Sottero ◽  
Gabriella Leonarduzzi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cholesterol Metabolism ◽  
Amyloid Β ◽  
Physiological Role ◽  
Cholesterol Oxidation ◽  
Peripheral Tissues ◽  
Functional Changes ◽  
Brain Cholesterol ◽  
The Impact

In recent decades, the impairment of cholesterol metabolism in the pathogenesis of Alzheimer’s disease (AD) has been intensively investigated, and it has been recognized to affect amyloid β (Aβ) production and clearance, tau phosphorylation, neuroinflammation and degeneration. In particular, the key role of cholesterol oxidation products, named oxysterols, has emerged. Brain cholesterol metabolism is independent from that of peripheral tissues and it must be preserved in order to guarantee cerebral functions. Among the cells that help maintain brain cholesterol homeostasis, astrocytes play a starring role since they deliver de novo synthesized cholesterol to neurons. In addition, other physiological roles of astrocytes are to modulate synaptic transmission and plasticity and support neurons providing energy. In the AD brain, astrocytes undergo significant morphological and functional changes that contribute to AD onset and development. However, the extent of this contribution and the role played by oxysterols are still unclear. Here we review the current understanding of the physiological role exerted by astrocytes in the brain and their contribution to AD pathogenesis. In particular, we focus on the impact of cholesterol dysmetabolism on astrocyte functions suggesting new potential approaches to develop therapeutic strategies aimed at counteracting AD development.

Amyloid β-peptide and Alzheimer's disease

2014 ◽  
Vol 56 ◽  
pp. 99-110 ◽  
Author(s):  
David Allsop ◽  
Jennifer Mayes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Strong Support ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Cascade Hypothesis ◽  
Sequence Of Events ◽  
Aβ Amyloid ◽  
Amyloid Cascade

One of the hallmarks of AD (Alzheimer's disease) is the formation of senile plaques in the brain, which contain fibrils composed of Aβ (amyloid β-peptide). According to the ‘amyloid cascade’ hypothesis, the aggregation of Aβ initiates a sequence of events leading to the formation of neurofibrillary tangles, neurodegeneration, and on to the main symptom of dementia. However, emphasis has now shifted away from fibrillar forms of Aβ and towards smaller and more soluble ‘oligomers’ as the main culprit in AD. The present chapter commences with a brief introduction to the disease and its current treatment, and then focuses on the formation of Aβ from the APP (amyloid precursor protein), the genetics of early-onset AD, which has provided strong support for the amyloid cascade hypothesis, and then on the development of new drugs aimed at reducing the load of cerebral Aβ, which is still the main hope for providing a more effective treatment for AD in the future.

Minimalistic Design Approach for Multi-Reactivity against Free Radicals and Metal-Free and Metal-Bound Amyloid-β Peptides: Redox-Based Substitutions of Benzene

2019 ◽  
Author(s):  
Mingeun Kim ◽  
Juhye Kang ◽  
Misun Lee ◽  
Jiyeon Han ◽  
Geewoo Nam ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Free Radicals ◽  
Amyloid Β ◽  
Design Strategy ◽  
Design Approach ◽  
Metal Free

We report a minimalistic redox-based design strategy for engineering compact molecules based on the simplest aromatic framework, benzene, with multi-reactivity against free radicals, metal-free amyloid-β, and metal-bound amyloid-β, implicated in the most common form of dementia, Alzheimer’s disease.

Neuroinflammation and Complexes of 17β -Hydroxysteroid Dehydrogenase type 10 - Amyloid β in Alzheimer's Disease

2013 ◽  
Vol 10 (2) ◽  
pp. 165-173 ◽  
Author(s):  
Zdena Kristofikova ◽  
Daniela Ripova ◽  
Ales Bartos ◽  
Marketa Bockova ◽  
Katerina Hegnerova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Hydroxysteroid Dehydrogenase

Microglia in Alzheimer’s Disease

2020 ◽  
Vol 17 (1) ◽  
pp. 29-43 ◽  
Author(s):  
Patrick Süß ◽  
Johannes C.M. Schlachetzki
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Current Knowledge ◽  
Imaging Techniques ◽  
Amyloid Β ◽  
Disease Stage ◽  
Disease Modifying Therapy ◽  
Transcriptomic Signature

: Alzheimer’s Disease (AD) is the most frequent neurodegenerative disorder. Although proteinaceous aggregates of extracellular Amyloid-β (Aβ) and intracellular hyperphosphorylated microtubule- associated tau have long been identified as characteristic neuropathological hallmarks of AD, a disease- modifying therapy against these targets has not been successful. An emerging concept is that microglia, the innate immune cells of the brain, are major players in AD pathogenesis. Microglia are longlived tissue-resident professional phagocytes that survey and rapidly respond to changes in their microenvironment. Subpopulations of microglia cluster around Aβ plaques and adopt a transcriptomic signature specifically linked to neurodegeneration. A plethora of molecules and pathways associated with microglia function and dysfunction has been identified as important players in mediating neurodegeneration. However, whether microglia exert either beneficial or detrimental effects in AD pathology may depend on the disease stage. : In this review, we summarize the current knowledge about the stage-dependent role of microglia in AD, including recent insights from genetic and gene expression profiling studies as well as novel imaging techniques focusing on microglia in human AD pathology and AD mouse models.

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