Microglial phagocytosis in aging and Alzheimer's disease

Gabandé‐Rodríguez, Enrique; Keane, Lily; Capasso, Melania

doi:10.1002/jnr.24419

Cited by 84 publications

(74 citation statements)

References 145 publications

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“…The synaptic pruning declines in the microglia during aging. The CX3CR1/CX3CL1 pathway is a pivotal signal path to initiate the "find me" phase, after which the microglia can bind with target synapses to perform phagocytosis and clearance [45]. In the present study, CX3CR1 −/− -SD mice showed better cognitive function, associated with higher synaptic density.…”

Section: Discussionsupporting

confidence: 54%

CX3CR1 modulates cognitive dysfunction induced by sleep deprivation

Xin¹,

Cheng²,

Xie³

et al. 2020

Preprint

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Background Sleep disorder-associated cognitive impairments are often accompanied by impaired synaptic plasticity. In the pathological process of sleep deprivation, microglia, as an important innate immune cell in central nervous system, are involved and mediate the synaptic pruning, in which the CX3C-chemokine receptor 1 receptor (CX3CR1) plays an indispensable role. In this study, the potential role of CX3CR1 in modulating the cognition decline during sleep deprivation was evaluated in terms of microglial neuroinflammation and synaptic pruning. Methods Middle-aged wild type C57BL/6 mice (WT) (13 months) and age-matched CX3CR1 -/- mice were either subjected to sleep deprivation (SD) or allowed normal sleep (S) for 8 h to mimic the pathophysiological changes of middle-aged people after staying up all night in real life. The hippocampus-dependent cognition was assessed by fear conditioning test. Mice brains were extracted for neuroinflammation and synaptic pruning studies. Data were analyzed by Student’s t-test and one-way analysis of variance (one-way ANOVA). Results The CX3CR1 deficiency mice differed from WT mice in many measures. CX3CR1 deficiency prevented SD-induced cognitive impairments, in which the levels of brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP-responsive element binding protein (p-CREB) were markedly increased in the hippocampus. Compared with the CX3CR1 -/- -S group, the CX3CR1 -/- -SD mice reported a markedly decreased microglial density in the dentate gyrus, notably-decreased levels of cellular oncogene fos (c-fos), and pro-inflammatory cytokines and increased levels of anti-inflammatory cytokines in the hippocampus, and a significant increase in the density of spines of the dentate gyrus area. Furthermore, the CX3CR1 -/- -SD group also showed a decreasing expression of microglial phagocytosis-related factors. Conclusion These findings suggest that CX3CR1 deficiency leads to different cerebral behaviors and responses to sleep deprivation. CX3CR1 deletion can alleviate the sleep deprivation-induced cognitive impairment. The inflammation-attenuating activity and the related modification of synaptic pruning are possible mechanism candidates, which indicate CX3CR1 as a candidate therapeutic target for the prevention of the sleep loss-induced cognitive impairments.

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Section: Discussionsupporting

confidence: 54%

CX3CR1 modulates cognitive dysfunction induced by sleep deprivation

Xin¹,

Cheng²,

Xie³

et al. 2020

Preprint

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show abstract

“…Several recent findings suggest that increased phagocytosis may be an aggravating factor in AD (Nizami et al , 2019). For one, microglial activation and subsequent phagocytosis of stressed but still viable neurons, has been postulated to enhance AD pathology (Gabandé-Rodríguez et al , 2020). Increased phagocytosis of apoptotic neurons has been observed in APOE4 overexpressing cells (Muth et al , 2019), and inhibiting microglial phagocytosis appears to prevent inflammatory neuronal death (Neher et al , 2011).…”

Section: Discussionmentioning

confidence: 99%

The Alzheimer’s disease protective P522R variant ofPLCG2, consistently enhances stimulus-dependent PLCγ2 activation, depleting substrate and altering cell function

Maguire

Menzies

Phillips

et al. 2020

Preprint

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Recent genome-wide association studies of Alzheimer's disease (AD) have identified variants implicating immune pathways in disease development. A rare coding variant of PLCG2, which encodes PLCγ2, shows a significant protective effect for AD (rs72824905, P522R, P=5.38x10 -10 , Odds Ratio = 0.68). Molecular dynamic modelling of the PLCγ2-R522 variant, situated within the auto-inhibitory domain of PLCγ2, suggests a structural change to the protein. Through CRISPR-engineering we have generated novel PLCG2-R522 harbouring human induced pluripotent cell lines (hiPSC) and a mouse knockin model, neither of which exhibits alterations in endogenous PLCG2 expression. Mouse microglia and macrophages and hiPSC-derived microglia-like cells with the R522 mutation, all demonstrate a consistent non-redundant hyperfunctionality in the context of normal expression of other PLC isoforms. This signalling alteration manifests as enhanced cellular Ca 2+ store release (~20-40% increase) in response to physiologically-relevant stimuli (e.g. Fc receptor ligation and Aβ oligomers). This hyperfunctionality resulted in increased PIP2 depletion in the cells with the PLCγ2-R522 variant after exposure to stimuli and reduced basal detection of PIP2 levels in vivo. These PLCγ2-R522 associated abnormalities resulted in impairments to phagocytosis (fungal and bacterial particles) and enhanced endocytosis (Aβ oligomers and dextran). PLCγ2 sits downstream of disease relevant pathways, such as TREM2 and CSF1R and alterations in its activity, direct impacts cell function, which in the context of the inherent drugability of enzymes such as PLCγ2, raise the prospect of manipulation of PLCγ2 as a therapeutic target in Alzheimer's Disease.

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“…The imbalance in these processes is a primary cause for a microglial switch towards a phenotype unable to control Aβ pathology and lacking protective functions [ 12 , 54 ]. In agreement, aging has been related to impaired microglial phagocytic ability and is considered a key risk factor in AD as well as other age-associated neurological disorders [ 55 , 56 ].…”

Section: Aβ Interactions At the Cell Surface: Where It All Startsmentioning

confidence: 96%

The Ambiguous Role of Microglia in Aβ Toxicity: Chances for Therapeutic Intervention

Merlo

Spampinato

Caruso

et al. 2020

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Amyloid-β (Aβ) has long been shown to be critical in Alzheimer’s disease pathophysiology. Microglia contributes to the earliest responses to Aβ buildup, by direct interaction through multiple receptors. Microglial cells operate Aβ clearance and trigger inflammatory/regenerative processes that take place in the long years of silent disease progression that precede symptomatic appearance. But in time and with aging, the fine balance between pro- and anti-inflammatory activity of microglia deranges, negatively impacting its Aβ-clearing ability. Furthermore, in recent years, microglial activation has proven to be much more complex than the mere dichotomic pro/antiinflammatory polarization previously accepted. Microglia can display a wide spectrum of phenotypes, which can even be mixed. On these bases, it is evident that while pharmacological intervention aiding microglia to prolong its ability to cope with Aβ buildup could be extremely relevant, its feasibility is hampered by such high complexity, which still needs to be completely understood.

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Microglial phagocytosis in aging and Alzheimer's disease

Cited by 84 publications

References 145 publications

CX3CR1 modulates cognitive dysfunction induced by sleep deprivation

CX3CR1 modulates cognitive dysfunction induced by sleep deprivation

The Alzheimer’s disease protective P522R variant ofPLCG2, consistently enhances stimulus-dependent PLCγ2 activation, depleting substrate and altering cell function

The Ambiguous Role of Microglia in Aβ Toxicity: Chances for Therapeutic Intervention

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