Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-β pathology

Spangenberg, Elizabeth E.; Lee, Rafael J.; Najafi, Allison R.; Rice, Rachel; Elmore, Monica R. P.; Blurton‐Jones, Mathew; West, Brian L.; Green, Kim N.

doi:10.1093/brain/aww016

Cited by 544 publications

(599 citation statements)

References 89 publications

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“…Another report involved the chronic treatment of 10-month-old 5XFAD mice with the CSF1R inhibitor PLX3397, an orally bioavailable agent that crosses the BBB and results in the actual elimination of around 80% of microglia [112]. At this age, these mice display extensive amyloid pathology and neuronal loss.…”

Section: Modulation Of Microglial and Astrocytic Response And Functionmentioning

confidence: 99%

Targeting neuroinflammation in Alzheimer’s disease: evidence for NSAIDs and novel therapeutics

Deardorff

Grossberg

2016

Expert Review of Neurotherapeutics

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There is an increasing recognition of the immune system as an important mediator in the pathogenesis of Alzheimer's disease (AD). As immune system modulators, non-steroidal anti-inflammatory drugs (NSAIDs) garnered initial enthusiasm from pre-clinical and epidemiologic studies as agents to reduce the risk of AD. Areas covered: This article will examine the evidence for the use of NSAIDs in AD by discussing the proposed mechanism of action, results from epidemiologic studies, and data from randomized controlled trials. In addition, a survey of several novel approaches to targeting inflammatory pathways currently in pre-clinical and clinical phases of development is presented. These agents primarily act to modulate microglial functioning, enhance amyloid-β phagocytosis, suppress potentially harmful pro-inflammatory responses, or enhance systemic immunity. Expert commentary: While long-term use of NSAIDs is associated with a reduced incidence of AD in epidemiologic studies, randomized controlled trials have not replicated these findings. Thus, NSAID use cannot currently be recommended either for primary prevention or treatment of AD. However, the available evidence does suggest that cognitively normal patients taking long-term courses of NSAIDs for other indications likely have a decreased risk of AD, which represents an important finding given the high prevalence of NSAID use among older adults.

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Section: Modulation Of Microglial and Astrocytic Response And Functionmentioning

confidence: 99%

Targeting neuroinflammation in Alzheimer’s disease: evidence for NSAIDs and novel therapeutics

Deardorff

Grossberg

2016

Expert Review of Neurotherapeutics

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“…In neurodegenerative disease or following traumatic brain injury, microglia can assume long‐lasting changes in morphology, densities, gene expression, and cytokine/chemokine production. Studies have indicated that these signals, when persistent in the brain, can lead to further harm (Dheen, Kaur, & Ling, 2007; Rice et al, 2015; Spangenberg et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

et al. 2018

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Microglia, the resident immune cell of the brain, can be eliminated via pharmacological inhibition of the colony‐stimulating factor 1 receptor (CSF1R). Withdrawal of CSF1R inhibition then stimulates microglial repopulation, effectively replacing the microglial compartment. In the aged brain, microglia take on a “primed” phenotype and studies indicate that this coincides with age‐related cognitive decline. Here, we investigated the effects of replacing the aged microglial compartment with new microglia using CSF1R inhibitor‐induced microglial repopulation. With 28 days of repopulation, replacement of resident microglia in aged mice (24 months) improved spatial memory and restored physical microglial tissue characteristics (cell densities and morphologies) to those found in young adult animals (4 months). However, inflammation‐related gene expression was not broadly altered with repopulation nor the response to immune challenges. Instead, microglial repopulation resulted in a reversal of age‐related changes in neuronal gene expression, including expression of genes associated with actin cytoskeleton remodeling and synaptogenesis. Age‐related changes in hippocampal neuronal complexity were reversed with both microglial elimination and repopulation, while microglial elimination increased both neurogenesis and dendritic spine densities. These changes were accompanied by a full rescue of age‐induced deficits in long‐term potentiation with microglial repopulation. Thus, several key aspects of the aged brain can be reversed by acute noninvasive replacement of microglia.

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“…In addition, amyloid associated microglia have been shown to be primarily derived from peripheral monocytes and may aggravate AD-like phenotypes (23,60). In addition, recent studies indicated that infiltrating peripheral monocytes clustered around amyloid plaques, but do not effectively clear plaques (61) and eliminating microglia did not affect amyloid load (62). We speculate that these observations may explain our findings that caspase-4 enhance microglial homing to plaques, yet failed to promote degradation or clearance.…”

Section: Discussionmentioning

confidence: 59%

The human-specificCASP4gene product contributes to Alzheimer-related synaptic and behavioural deficits

Kajiwara¹,

McKenzie

Dorr

et al. 2016

Hum. Mol. Genet.

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Recent studies have indicated that innate immune signalling molecules are involved in late-onset Alzheimer's disease (LOAD) risk. Amyloid beta (Ab) accumulates in AD brain, and has been proposed to act as a trigger of innate immune responses. Caspase-4 is an important part of the innate immune response. We recently characterized transgenic mice carrying human CASP4, and observed that the mice manifested profound innate immune responses to lipopolysaccharide (LPS). Since these inflammatory processes are important in the aetiology of AD, we have now analysed the correlation of expression of caspase-4 in human brain with AD risk genes, and studied caspase-4 effects on AD-related phenotypes in APPswe/PS1deltaE9 (APP/PS1) mice. We observed that the expression of caspase-4 was strongly correlated with AD risk genes including TYROBP, TREM2, CR1, PSEN1, MS4A4A and MS4A6A in LOAD brains. Caspase-4 expression was upregulated in CASP4/APP/PS1 mice in a region-specific manner, including hippocampus and prefrontal cortex. In APP/PS1 mice, caspase-4 expression led to impairments in the reversal phase of a Barnes maze task and in hippocampal synaptic plasticity, without affecting soluble or aggregated Ab levels. Caspase-4 was expressed predominantly in microglial cells, and in the presence of CASP4, more microglia were clustered around amyloid plaques. Furthermore, our data indicated that caspase-4 modulates microglial cells in a manner that increases proinflammatory processes. We propose that microglial caspase-4 expression contributes to the cognitive impairments in AD, and that further study of caspase-4 will enhance our understanding of AD pathogenesis and may lead to novel therapeutic targets in AD.

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Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-β pathology

Cited by 544 publications

References 89 publications

Targeting neuroinflammation in Alzheimer’s disease: evidence for NSAIDs and novel therapeutics

Targeting neuroinflammation in Alzheimer’s disease: evidence for NSAIDs and novel therapeutics

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

The human-specificCASP4gene product contributes to Alzheimer-related synaptic and behavioural deficits

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