γ‐Secretase in microglia – implications for neurodegeneration and neuroinflammation

Walter, Jochen; Kemmerling, Nadja; Wunderlich, Patrick; Glebov, Konstantin

doi:10.1111/jnc.14224

Cited by 16 publications

(13 citation statements)

References 117 publications

(173 reference statements)

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“…We demonstrate here that the PSEN2 N141I variant results in decreased γ -secretase activity in microglia despite the presence of one wildtype Psen2 and two wild type Psen1 alleles. Given that the γ -secretase mediated endoproteolytic cleavage of several substrates including Notch1 and TREM2 regulate innate immune cell signaling [ 19, 47 ], we propose that the PS2 N141I mediated disruption of normal enzymatic activity leads to a loss of microglial homeostasis in EOFAD patients. Consequently, in addition to aberrant Aβ production, PSEN2 disease associated variants would impair the normal innate immune response to protein aggregates and promote an exaggerated, injurious inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

“…Presenilins are expressed ubiquitously and regulate a large array of cellular functions through proteolytic and non-enzymatic actions [ 19, 20 ]. As the enzymatic component of the γ -secretase complex, PSs cleave dozens of substrates beyond AβPP, including those relevant to neural and peripheral immune cells [ 21, 22 ].…”

Section: Introductionmentioning

confidence: 99%

“…As the enzymatic component of the γ -secretase complex, PSs cleave dozens of substrates beyond AβPP, including those relevant to neural and peripheral immune cells [ 21, 22 ]. Substrates of γ -secretase and PS2 activity that regulate immune cell function include TREM2, TNF Type Receptor 1, IL-1 receptor, IL-6 receptor, CX3CL1, and CSF1R [ 19, 23–25 ]. EOFAD associated PSEN variants compromise γ -secretase function and lead to a biochemical “loss-of-function”, causing dominant negative interference with the wildtype allele or reduced PS expression [ 26–30 ].…”

Section: Introductionmentioning

confidence: 99%

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Early-Onset Familial Alzheimer Disease Variant PSEN2 N141I Heterozygosity is Associated with Altered Microglia Phenotype

Fung

Smith

Prater

et al. 2020

JAD

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Background: Early-onset familial Alzheimer disease (EOFAD) is caused by heterozygous variants in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), and APP genes. Decades after their discovery, the mechanisms by which these genes cause Alzheimer’s disease (AD) or promote AD progression are not fully understood. While it is established that presenilin (PS) enzymatic activity produces amyloid-β (Aβ), PSs also regulate numerous other cellular functions, some of which intersect with known pathogenic drivers of neurodegeneration. Accumulating evidence suggests that microglia, resident innate immune cells in the central nervous system, play a key role in AD neurodegeneration. Objective: Previous work has identified a regulatory role for PS2 in microglia. We hypothesized that PSEN2 variants lead to dysregulated microglia, which could further contribute to disease acceleration. To mimic the genotype of EOFAD patients, we created a transgenic mouse expressing PSEN2 N141I on a mouse background expressing one wildtype PS2 and two PS1 alleles. Results: Microglial expression of PSEN2 N141I resulted in impaired γ-secretase activity as well as exaggerated inflammatory cytokine release, NFκB activity, and Aβ internalization. In vivo, PS2 N141I mice showed enhanced IL-6 and TREM2 expression in brain as well as reduced branch number and length, an indication of “activated” morphology, in the absence of inflammatory stimuli. LPS intraperitoneal injection resulted in higher inflammatory gene expression in PS2 N141I mouse brain relative to controls. Conclusion: Our findings demonstrate that PSEN2 N141I heterozygosity is associated with disrupted innate immune homeostasis, suggesting EOFAD variants may promote disease progression through non-neuronal cells beyond canonical dysregulated Aβ production.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Early-Onset Familial Alzheimer Disease Variant PSEN2 N141I Heterozygosity is Associated with Altered Microglia Phenotype

Fung

Smith

Prater

et al. 2020

JAD

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“…For example, the diol 19,20-dihydroxydocosapentaenoic acid (DHDP) is generated by the sEH from the epoxide 19,20-epoxydocosapentaenoic acid (19,20-EDP), which is in turn generated by CYP enzymes from DHA. This is relevant as 19,20-DHDP, generated by Müller glia cells, regulates physiological angiogenesis via the direct inhibition of the γ-secretase 26 , which is involved in the cleavage and activation of Notch signaling 27 . More recently, however, much higher concentrations of the same metabolite were detected in diabetic human and murine retinas and linked with pericyte loss, acellular capillary formation and breakdown of the blood retinal barrier (BRB).…”

Section: Introductionmentioning

confidence: 99%

Protective effect of Soluble Epoxide Hydrolase Inhibition in Retinal Vasculopathy associated with Polycystic Kidney Disease

Lin¹,

Hu²,

Schlotterer³

et al. 2020

Theranostics

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Rationale: Vasoregression secondary to glial activation develops in various retinal diseases, including retinal degeneration and diabetic retinopathy. Photoreceptor degeneration and subsequent retinal vasoregression, characterized by pericyte loss and acellular capillary formation in the absence diabetes, are also seen in transgenic rats expressing the polycystic kidney disease (PKD) gene. Activated Müller glia contributes to retinal vasodegeneration, at least in part via the expression of the soluble epoxide hydrolase (sEH). Given that an increase in sEH expression triggered vascular destabilization in diabetes, and that vasoregression is similar in diabetic mice and PKD rats, the aim of the present study was to determine whether sEH inhibition could prevent retinal vasoregression in the PKD rat. Methods: One-month old male homozygous transgenic PKD rats were randomly allocated to receive vehicle or a sEH inhibitor (sEH-I; Sar5399, 30 mg/kg) for four weeks. Wild-type Sprague-Dawley (SD) littermates received vehicle as controls. Retinal sEH expression and activity were measured by Western blotting and LC-MS, and vasoregression was quantified in retinal digestion preparations. Microglial activation and immune response cytokines were assessed by immunofluorescence and quantitative PCR, respectively. 19,20-dihydroxydocosapentaenoic acid (19,20-DHDP) mediated Notch signaling, microglial activation and migration were assessed in vivo and in vitro . Results: This study demonstrates that sEH expression and activity were increased in PKD retinae, which led to elevated production of 19,20-DHDP and the depression of Notch signaling. The latter changes elicited pericyte loss and the recruitment of CD11b + /CD74 + microglia to the perivascular region. Microglial activation increased the expression of immune-response cytokines, and reduced levels of Notch3 and delta-like ligand 4 (Dll4). Treatment with Sar5399 decreased 19,20-DHDP generation and increased Notch3 expression. Sar5399 also prevented vasoregression by reducing pericyte loss and suppressed microglial activation as well as the expression of immune-response cytokines. Mechanistically, the activation of Notch signaling by Dll4 maintained a quiescent microglial cell phenotype, i.e. reduced both the surface presentation of CD74 and microglial migration. In contrast, in retinal explants, 19,20-DHDP and Notch inhibition both promoted CD74 expression and reversed the Dll4-induced decrease in migration. Conclusions: Our data indicate that 19,20-DHDP-induced alterations in Notch-signaling result in microglia activation and pericyte loss and contribute to retinal vasoregression in polycystic kidney disease. Moreover, sEH inhibition can ameliorate vasoregression through reduced activity of inflammatory microglia. sEH inhibition is thus an attractive new therapeutic approach to prevent retinal vas...

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“…Amandine Grimm and Anne Eckert (Grimm and Eckert ) illustrate the pivotal role of mitochondria in the brain, mitochondrial dynamics in the course of aging, and dysfunction in neurodegeneration taking into account also sexual dimorphism. Jochen Walter and colleagues (Walter ) refer to the fact that γ‐secretase besides amyloid precursor protein (APP) cleaves a multitude of additional protein substrates and summarize recent evidence that demonstrates an involvement of the enzyme in the regulation of microglial function.…”

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confidence: 99%

Beyond Amyloid – Widening the View on Alzheimer's Disease

Behl

Ziegler

2017

Journal of Neurochemistry

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For 25 years, the amyloid cascade hypothesis, based on the finding that mutations in the amyloid precursor protein are closely linked to familial forms of Alzheimer's disease (AD), dominated the research on this disease. Recent failures of clinical anti-amyloidogenic trials, however, substantially support the reasoning (i) that the pathomechanisms that trigger familial AD, namely the generation, aggregation, and deposition of amyloid beta, cannot necessarily be extrapolated to sporadic cases and (ii) that amyloid beta represents a prominent histopathological feature in AD but not its exclusive causative factor. In autumn 2016, the Volkswagen Foundation hosted the Herrenhausen Symposium 'Beyond Amyloid - Widening the View on Alzheimer's Disease' in Hannover, Germany, to bring together current knowledge on cellular and molecular processes that contribute to AD pathogenesis independent of or alongside with the amyloid biochemistry. The following mini review series was authored by key speakers at the meeting, and highlights some of the mechanisms potentially involved in AD etiology that provide alternative viewpoints and mechanisms beyond the amyloid cascade hypothesis. This article is part of the series "Beyond Amyloid".

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γ‐Secretase in microglia – implications for neurodegeneration and neuroinflammation

Cited by 16 publications

References 117 publications

Early-Onset Familial Alzheimer Disease Variant PSEN2 N141I Heterozygosity is Associated with Altered Microglia Phenotype

Early-Onset Familial Alzheimer Disease Variant PSEN2 N141I Heterozygosity is Associated with Altered Microglia Phenotype

Protective effect of Soluble Epoxide Hydrolase Inhibition in Retinal Vasculopathy associated with Polycystic Kidney Disease

Beyond Amyloid – Widening the View on Alzheimer's Disease

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