β-Catenin Pathway Is Involved in TREM2-Mediated Microglial Survival

Zulfiqar, Shadaan; Tanriöver, Gaye

doi:10.1523/jneurosci.1087-17.2017

Cited by 5 publications

(3 citation statements)

References 23 publications

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“…2-2 B, available at https:// doi.org/10.1523/JNEUROSCI.1871-19.2019.f2-2). The reduced expression of Wnt-related signaling components and regulators in PS2APP;Trem2 ko microglia may be consistent with previous reports of coordinated signaling between Trem2 and ␤-catenin pathways within microglia (Zheng et al, 2017;Zulfiqar and Tanriöver, 2017).…”

Section: Trem2-dependent Induction Of the Proliferation And Neurodegesupporting

confidence: 92%

Trem2 Deletion Reduces Late-Stage Amyloid Plaque Accumulation, Elevates the Aβ42:Aβ40 Ratio, and Exacerbates Axonal Dystrophy and Dendritic Spine Loss in the PS2APP Alzheimer's Mouse Model

Meilandt¹,

Ngu²,

et al. 2020

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TREM2 is an Alzheimer's disease (AD) risk gene expressed in microglia. To study the role of Trem2 in a mouse model of ␤-amyloidosis, we compared PS2APP transgenic mice versus PS2APP mice lacking Trem2 (PS2APP;Trem2 ko) at ages ranging from 4 to 22 months. Microgliosis was impaired in PS2APP;Trem2 ko mice, with Trem2-deficient microglia showing compromised expression of proliferation/ Wnt-related genes and marked accumulation of ApoE. Plaque abundance was elevated in PS2APP;Trem2 ko females at 6-7 months; but by 12 or 19-22 months of age, it was notably diminished in female and male PS2APP;Trem2 ko mice, respectively. Across all ages, plaque morphology was more diffuse in PS2APP;Trem2 ko brains, and the A␤42:A␤40 ratio was elevated. The amount of soluble, fibrillar A␤ oligomers also increased in PS2APP;Trem2 ko hippocampi. Associated with these changes, axonal dystrophy was exacerbated from 6 to 7 months onward in PS2APP;Trem2 ko mice, notwithstanding the reduced plaque load at later ages. PS2APP;Trem2 ko mice also exhibited more dendritic spine loss around plaque and more neurofilament light chain in CSF. Thus, aggravated neuritic dystrophy is a more consistent outcome of Trem2 deficiency than amyloid plaque load, suggesting that the microglial packing of A␤ into dense plaque is an important neuroprotective activity.

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Section: Trem2-dependent Induction Of the Proliferation And Neurodegesupporting

confidence: 92%

Trem2 Deletion Reduces Late-Stage Amyloid Plaque Accumulation, Elevates the Aβ42:Aβ40 Ratio, and Exacerbates Axonal Dystrophy and Dendritic Spine Loss in the PS2APP Alzheimer's Mouse Model

Meilandt¹,

Ngu²,

et al. 2020

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“…TREM2 and β-Catenin may have a critical role to allow the survival and proliferation of microglia in the CSF1R cKO APP mice. TREM2 is an immunoreceptor expressed in the brain by microglia [23]; it activates survival pathway via β-Catenin [23,25,29,50]. Moreover, the TREM2/β-Catenin pathway is important for microglial survival and proliferation [50].…”

Section: Discussionmentioning

confidence: 99%

Conditional genetic deletion of CSF1 receptor in microglia ameliorates the physiopathology of Alzheimer’s disease

et al. 2021

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Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia in the world. Microglia are the innate immune cells of CNS; their proliferation, activation, and survival in pathologic and healthy brain have previously been shown to be highly dependent on CSF1R. Methods Here, we investigate the impact of such receptor on AD etiology and microglia. We deleted CSF1R using Cre/Lox system; the knockout (KO) is restricted to microglia in the APP/PS1 mouse model. We induced the knockout at 3 months old, before plaque formation, and evaluated both 6- and 8-month-old groups of mice. Results Our findings demonstrated that CSF1R KO did not impair microglial survival and proliferation at 6 and 8 months of age in APP cKO compared to their littermate-control groups APPSwe/PS1. We have also shown that cognitive decline is delayed in CSF1R-deleted mice. Ameliorations of AD etiology are associated with a decrease in plaque volume in the cortex and hippocampus area. A compensating system seems to take place following the knockout, since TREM2/β-Catenin and IL-34 expression are significantly increased. Such a compensatory mechanism may promote microglial survival and phagocytosis of Aβ in the brain. Conclusions Our results provide new insights on the role of CSF1R in microglia and how it interacts with the TREM2/β-Catenin and IL-34 system to clear Aβ and ameliorates the physiopathology of AD.

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“…TREM2 and β-Catenin may have a critical role to allow the survival and proliferation of microglia in the CSF1R cKO APP mice. TREM2 is an immunoreceptor expressed in the brain by microglia (23) and activates survival pathway via β-Catenin (23,25,29,43). Moreover, TREM2/β-Catenin pathway is important for microglial survival and proliferation (43).…”

Section: Discussionmentioning

confidence: 99%

Conditional genetic deletion of CSF1 receptor in microglia ameliorates the physiopathology of Alzheimer’s disease

Pons

Lévesque²,

Plande

et al. 2020

Preprint

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BackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia in the world. Microglia are the innate immune cells of CNS, their proliferation, activation and survival in pathologic and healthy brain have previously been shown to be highly dependent on CSF1R.MethodsHere we investigate the impact of such receptor on AD etiology and microglia. We deleted CSF1R using Cre/Lox system, the knock-out (KO) is restricted to microglia in the APP/PS1 mouse model. We induced the knock-out at 3-month-old, before plaque formation and evaluated both 6 and 8-month-old groups of mice.ResultsOur findings demonstrated that CSF1R KO did not impair microglial survival and proliferation at 6 and 8 months of age in APP cKO compared to their littermate controls groups APPSwe/PS1. We have also shown that cognitive decline is delayed in CSF1R-deleted mice. Ameliorations of AD etiology is associated with a decrease in plaque volume in cortex and hippocampus area. A compensating system seems to take place following the knock-out, since TREM2/β-Catenin and IL-34 expression are significantly increased. Such a compensatory mechanism may promote microglial survival and phagocytosis of Aβ in the brain.ConclusionsOur results provide new insights on the role of CSF1R in microglia and how it interacts with the TREM2/β-Catenin and IL-34 system to clear Aβ and ameliorates the physiopathology of AD.

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β-Catenin Pathway Is Involved in TREM2-Mediated Microglial Survival

Cited by 5 publications

References 23 publications

Trem2 Deletion Reduces Late-Stage Amyloid Plaque Accumulation, Elevates the Aβ42:Aβ40 Ratio, and Exacerbates Axonal Dystrophy and Dendritic Spine Loss in the PS2APP Alzheimer's Mouse Model

Trem2 Deletion Reduces Late-Stage Amyloid Plaque Accumulation, Elevates the Aβ42:Aβ40 Ratio, and Exacerbates Axonal Dystrophy and Dendritic Spine Loss in the PS2APP Alzheimer's Mouse Model

Conditional genetic deletion of CSF1 receptor in microglia ameliorates the physiopathology of Alzheimer’s disease

Conditional genetic deletion of CSF1 receptor in microglia ameliorates the physiopathology of Alzheimer’s disease

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