scholarly journals Phosphoproteomics identifies microglial Siglec-F inflammatory response during neurodegeneration

2020 ◽  
Author(s):  
Nader Morshed ◽  
William T. Ralvenius ◽  
Alexi Nott ◽  
L. Ashley Watson ◽  
Felicia H. Rodriguez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inflammatory Response ◽  
Mouse Models ◽  
Microglial Activation ◽  
Phosphorylation Site ◽  
Amyloid Β ◽  
Similar Response ◽  
List Type ◽  
Reactive Microglia

SummaryAlzheimer’s disease (AD) is characterized by the appearance of amyloid-β plaques, neurofibrillary tangles, and inflammation in brain regions involved in memory. Using mass spectrometry, we have quantified the phosphoproteome of the CK-p25, 5XFAD, and Tau P301S mouse models of neurodegeneration. We identified a shared response involving Siglec-F which was upregulated on a subset of reactive microglia. The human paralog Siglec-8 was also upregulated on microglia in AD. Siglec-F and Siglec-8 were upregulated following microglial activation with interferon gamma (IFNγ) in BV-2 cell line and human stem-cell derived microglia models. Siglec-F overexpression activates an endocytic and pyroptotic inflammatory response in BV-2 cells, dependent on its sialic acid substrates and immunoreceptor tyrosine-based inhibition motif (ITIM) phosphorylation sites. Related human Siglecs induced a similar response in BV-2 cells. Collectively, our results point to an important role for mouse Siglec-F and human Siglec-8 in regulating microglial activation during neurodegeneration.HighlightsPhosphoproteomics analysis of CK-p25, 5XFAD, and Tau P301S mouse models finds dysregulated signaling networks associated with Alzheimer’s disease pathologies.A phosphorylation site on Siglec-F is found to be upregulated across all three models of disease.Expression of Siglec-F and its human paralog Siglec-8 is increased in reactive microglia.Overexpression of Siglec-F and Siglec-8 in vitro drives an endocytic and pyroptotic inflammatory response.In BriefPhosphoproteome signaling changes associated with Alzheimer’s disease (AD) are poorly characterized. Here, Morshed et al. apply phosphoproteomics to mouse models of AD to uncover a novel microglial receptor, Siglec-F, that is upregulated on a subset of inflammatory microglia across models of neurodegeneration. The human paralog, Siglec-8 is also found to be upregulated in late-onset AD microglia. Overexpression of Siglec-F and related human Siglecs activates pro-inflammatory signaling responses in BV-2 cells.

Astrocyte Reactivity in Alzheimer’s Disease: Therapeutic Opportunities to Promote Repair

2021 ◽  
Vol 18 ◽  
Author(s):  
Nazanin Mirzaei ◽  
Nicola Davis ◽  
Tsz Wing Chau ◽  
Magdalena Sastre
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Mouse Models ◽  
Neurodegenerative Disorders ◽  
Amyloid Β ◽  
Neuroprotective Effects ◽  
Synaptic Density ◽  
Inflammatory Profile

: Astrocytes are fast climbing the ladder of importance in neurodegenerative disorders, particularly in Alzheimer’s disease (AD), with the prominent presence of reactive astrocytes sur- rounding amyloid β- plaques, together with activated microglia. Reactive astrogliosis, implying morphological and molecular transformations in astrocytes, seems to precede neurodegeneration, suggesting a role in the development of the disease. Single-cell transcriptomics has recently demon- strated that astrocytes from AD brains are different from “normal” healthy astrocytes, showing dys- regulations in areas such as neurotransmitter recycling, including glutamate and GABA, and im- paired homeostatic functions. However, recent data suggest that the ablation of astrocytes in mouse models of amyloidosis results in an increase in amyloid pathology as well as in the inflammatory profile and reduced synaptic density, indicating that astrocytes mediate neuroprotective effects. The idea that interventions targeting astrocytes may have great potential for AD has therefore emerged, supported by a range of drugs and stem cell transplantation studies that have successfully shown a therapeutic effect in mouse models of AD. In this article, we review the latest reports on the role and profile of astrocytes in AD brains and how manipulation of astrocytes in animal mod- els has paved the way for the use of treatments enhancing astrocytic function as future therapeutic avenues for AD.

scholarly journals Amyloid-β protein modulates the perivascular clearance of neuronal apolipoprotein E in mouse models of Alzheimer’s disease

2011 ◽  
Vol 118 (5) ◽  
pp. 699-712 ◽  
Author(s):  
Harshvardhan Rolyan ◽  
Ann Caroline Feike ◽  
Ajeet Rijal Upadhaya ◽  
Andreas Waha ◽  
Tom Van Dooren ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Apolipoprotein E ◽  
Mouse Models ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Β Protein

scholarly journals Diverse Brain Myeloid Expression Profiles Reveal Distinct Microglial Activation States and Aspects of Alzheimer’s Disease Not Evident in Mouse Models

Cell Reports ◽  
2018 ◽  
Vol 22 (3) ◽  
pp. 832-847 ◽  
Author(s):  
Brad A. Friedman ◽  
Karpagam Srinivasan ◽  
Gai Ayalon ◽  
William J. Meilandt ◽  
Han Lin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Microglial Activation ◽  
Expression Profiles

Reduced amyloid-β degradation in early Alzheimer's disease but not in the APPswePS1dE9 and 3xTg-AD mouse models

Aging Cell ◽  
2013 ◽  
Vol 12 (3) ◽  
pp. 499-507 ◽  
Author(s):  
Anita Stargardt ◽  
Judith Gillis ◽  
Willem Kamphuis ◽  
Anne Wiemhoefer ◽  
Lieneke Kooijman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Amyloid Β ◽  
Early Alzheimer’S Disease

scholarly journals Ageing-associated myelin dysfunction drives amyloid deposition in mouse models of Alzheimer's disease

2021 ◽  
Author(s):  
Constanze Depp ◽  
Ting Sun ◽  
Andrew Octavian Sasmita ◽  
Lena Spieth ◽  
Stefan A. Berghoff ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Mouse Models ◽  
Structural Integrity ◽  
Amyloid Β ◽  
Amyloid Deposition ◽  
Structural Defects ◽  
Light Sheet Microscopy ◽  
Brain Ageing

The prevalence of Alzheimer's disease (AD), the leading cause of dementia, shows a strict age-dependency, but why ageing constitutes the main risk factor for this disease is still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths, the latter associated with secondary neuroinflammation. Since oligodendrocytes support axonal and neuronal health, we hypothesised that ageing-associated loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the primary neuropathological hallmark of AD. Here, we show that in AD mouse models different genetically induced defects of myelin integrity or demyelinating injuries are indeed potent drivers of amyloid deposition in vivo, quantified by whole brain light sheet microscopy. Conversely, the lack of myelin in the forebrain provides protection against plaque deposition. Mechanistically, we find that myelin dysfunction causes the accumulation of the Aβ producing machinery within axonal swellings and increases cortical amyloid precursor protein (APP) cleavage. Surprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia but show a disease-associated microglia (DAM)-like signature as revealed by bulk and single cell transcriptomics. These activated microglia, however, are primarily engaged with myelin, preventing the protective reactions of microglia to Aβ plaques. Our data suggest a working model, in which age-dependent structural defects of myelin promote plaque formation, directly and indirectly, and are thus an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay AD.

scholarly journals The Temporal Relationships between White Matter Hyperintensities, Neurodegeneration, Amyloid β, and Cognition

2020 ◽  
Author(s):  
Mahsa Dadar ◽  
Richard Camicioli ◽  
Simon Duchesne ◽  
D. Louis Collins ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Cognitive Decline ◽  
White Matter Hyperintensities ◽  
Amyloid Β ◽  
Disease Assessment ◽  
White Matter Hyperintensity ◽  
List Type ◽  
Temporal Relationships

ABSTRACTINTRODUCTIONCognitive decline in Alzheimer’s disease is associated with amyloid-β accumulation, neurodegeneration and cerebral small vessel disease, but the temporal relationships between these factors is not well established.METHODSData included white matter hyperintensity (WMH) load, grey matter (GM) atrophy and Alzheimer’s Disease Assessment Scale-Cognitive-Plus (ADAS13) scores for 720 participants and cerebrospinal fluid amyloid (Aβ1-42) for 461 participants from the Alzheimer’s Disease Neuroimaging Initiative. Linear regressions were used to assess the relationships between baseline WMH, GM, and Aβ1-42 to changes in WMH, GM, Aβ1-42, and cognition at one-year follow-up.RESULTSBaseline WMHs and Aβ1-42 predicted WMH increase and GM atrophy. Baseline WMHs, GM, and Aβ1-42 predicted worsening cognition. Only baseline Aβ1-42 predicted change in Aβ1-42.DISCUSSIONBaseline WMHs lead to greater future GM atrophy and cognitive decline, suggesting that WM damage precedes neurodegeneration and cognitive decline. Baseline Aβ1-42 predicted WMH increase, suggesting a potential role of amyloid in WM damage.Research in ContextSystematic Review: Both amyloid β and neurodegeneration are primary pathologies in Alzheimer’s disease. White matter hyperintensities (indicative of presence of cerebrovascular disease) might also be part of the pathological changes in Alzheimer’s. However, the temporal relationship between white matter hyperintensities, amyloid β, neurodegeneration, and cognitive decline is still unclear.Interpretation: Our results establish a potential temporal order between white matter hyperintensities, amyloid β, neurodegeneration, and cognitive decline, showing that white matter hyperintensities precede neurodegeneration and cognitive decline. The results provide some evidence that amyloid β deposition, in turn, precedes accumulation of white matter hyperintensities.Future Directions: The current findings reinforce the need for future longitudinal investigations of the mechanisms through which white matter hyperintensities impact the aging population in general and Alzheimer’s disease patients, in particular.

scholarly journals Programmed Cell Death Protein 1 Blockade Reduces Glycogen Synthase Kinase 3β Activity and Tau Hyperphosphorylation in Alzheimer’s Disease Mouse Models

2021 ◽  
Vol 9 ◽  
Author(s):  
Yulian Zou ◽  
Chen-Ling Gan ◽  
Zhiming Xin ◽  
Hai-Tao Zhang ◽  
Qi Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Mouse Models ◽  
Glycogen Synthase ◽  
Neuronal Damage ◽  
Amyloid Β ◽  
Glycogen Synthase Kinase ◽  
Tau Hyperphosphorylation

Alzheimer’s disease (AD) is a central nervous system degenerative disease, with no effective treatment to date. Administration of immune checkpoint inhibitors significantly reduces neuronal damage and tau hyperphosphorylation in AD, but the specific mechanism is unclear. Here, we found that programmed cell death-receptor 1 (PD1) and its ligand PDL1 were induced by an intracerebroventricular injection of amyloid-β; they were significantly upregulated in the brains of APP/PS1, 5×FAD mice and in SH-SY5Y-APP cell line compared with control. The PD1 and PDL1 levels positively correlated with the glycogen synthase kinase 3 beta (GSK3β) activity in various AD mouse models, and the PDL1-GSK3β immune complex was found in the brain. The application of PD1-blocking antibody reduced tau hyperphosphorylation and GSK3β activity and prevented memory impairments. Mechanistically, we identified PD1 as a critical regulator of GSK3β activity. These results suggest that the immune regulation of the PD1/PDL1 axis is closely involved in AD.

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