Genetic Inhibition of sFRP3 Prevents Glial Reactivity in a Mouse Model of Accelerated Aging
2
조회
0
다운로드
1
인용
0
참고문헌
키워드
초록
Purpose: Aging is the most significant risk factor for neurodegenerative disorders that are typified by cognitive deficits. Our recent work utilizing BubR1 hypomorphic (BubR1H/H) mice, an accelerated aging model, has revealed that genetic inhibition of the endogenous Wnt pathway inhibitor secreted frizzled related protein 3 (sFRP3) plays a neuroprotective role. Neuroinflammation has been suggested as a pathological hallmark of age-related neurodegeneration mediating cognitive impairment. However, whether sFRP3 inhibition has a neuroprotective effect on neuroinflammatory gliosis in BubR1H/H mice is unknown. Methods: To investigate neuroprotection from aging-related neuroinflammation by sFRP3 in vivo, we generated double Bub R1H/H;sfrp3 knockout mice and performed immunohistological analysis with cell type-specific markers for astrocytes (glial fibrillary acidic protein), and microglia (ionized calcium-binding adapter molecule 1). Given that the hippocampus is a brain structure critical for learning and memory, and is uniquely affected in aging-related neurodegeneration, we evaluated morphological changes on astrocytes and microglia via confocal imaging. Results: We demonstrate that BubR1H/H mice exhibit significantly increased levels of astrogliosis and an increased trend of microglial activation in the hilus and molecular layer of the young adult hippocampus, thus suggesting that BubR1 insufficiency accelerates glial reactivity. Importantly, our results further show that genetic inhibition of sFRP3 significantly recovers the astrogliosis and microglial activation observed in BubR1H/H mice, suggesting a critical neuroprotective role for sFRP3 in age-related neuroinflammation. Conclusions: Our findings suggest that sFRP3 inhibition may represent a novel therapeutic strategy for neurodegeneration.
Abstract
Purpose: Aging is the most significant risk factor for neurodegenerative disorders that are typified by cognitive deficits. Our recent work utilizing BubR1 hypomorphic (BubR1H/H) mice, an accelerated aging model, has revealed that genetic inhibition of the endogenous Wnt pathway inhibitor secreted frizzled related protein 3 (sFRP3) plays a neuroprotective role. Neuroinflammation has been suggested as a pathological hallmark of age-related neurodegeneration mediating cognitive impairment. However, whether sFRP3 inhibition has a neuroprotective effect on neuroinflammatory gliosis in BubR1H/H mice is unknown. Methods: To investigate neuroprotection from aging-related neuroinflammation by sFRP3 in vivo, we generated double Bub R1H/H;sfrp3 knockout mice and performed immunohistological analysis with cell type-specific markers for astrocytes (glial fibrillary acidic protein), and microglia (ionized calcium-binding adapter molecule 1). Given that the hippocampus is a brain structure critical for learning and memory, and is uniquely affected in aging-related neurodegeneration, we evaluated morphological changes on astrocytes and microglia via confocal imaging. Results: We demonstrate that BubR1H/H mice exhibit significantly increased levels of astrogliosis and an increased trend of microglial activation in the hilus and molecular layer of the young adult hippocampus, thus suggesting that BubR1 insufficiency accelerates glial reactivity. Importantly, our results further show that genetic inhibition of sFRP3 significantly recovers the astrogliosis and microglial activation observed in BubR1H/H mice, suggesting a critical neuroprotective role for sFRP3 in age-related neuroinflammation. Conclusions: Our findings suggest that sFRP3 inhibition may represent a novel therapeutic strategy for neurodegeneration.
참고문헌 (23)
- Stern Y, "Cognitive reserve in ageing and Alzheimer’s disease", Lancet Neurol, 11, pp.1006~1012 (2012)
- García-Castillo H, "Clinical and genetic heterogeneity in patients with mosaic variegated aneuploidy : Delineation of clinical subtypes", Am J Med Genet A, 146A, pp.1687~1695 (2008)
- Matsuura S, "Monoallelic BUB1B mutations and defective mitoticspindle checkpoint in seven families with premature chromatid separation(PCS)syndrome", Am J Med Genet A, 140, pp.358~367 (2006)
- Baker DJ, "Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan", Nat Cell Biol, 15, pp.96~102 (2013)
- Baker DJ, "BubR1 insufficiency causes early onset of agingassociated phenotypes and infertility in mice", Nat Genet, 36, pp.744~749 (2004)
- Yang Z, "Age-related decline in BubR1 impairs adult hippocampal neurogenesis", Aging Cell, 16, pp.598~601 (2017)
- Choi CI, "The progeroid gene BubR1 regulates axon myelination and motor function", Aging (2016)
- Chang Hoon Cho, "BubR1 Insufficiency Impairs Affective Behavior and Memory Function in Mice", International Neurourology Journal, 22, pp.122~130 (2018), 대한배뇨장애요실금학회
- Komiya Y, "Wnt signal transduction pathways", Organogenesis, 4, pp.68~75 (2008)
- Hussaini SM, "Wnt signaling in neuropsychiatric disorders : Ties with adult hippocampal neurogenesis and behavior", Neurosci Biobehav Rev, 47, pp.369~383 (2014)
- Inestrosa NC, "Wnt signaling in the nervous system and in Alzheimer’s disease", J Mol Cell Biol, 6, pp.64~74 (2014)
- Jang MH, "Secreted frizzled-related protein 3 regulates activity-dependent adult hippocampal neurogenesis", Cell Stem Cell, 12, pp.215~223 (2013)
- Jang MH, "Secreted frizzled-related protein 3(sFRP3)regulates antidepressant responses in mice and humans", Mol Psychiatry, 18, pp.957~958 (2013)
- Seib DR, "Loss of Dickkopf-1 restores neurogenesis in old age and counteracts cognitive decline", Cell Stem Cell, 12, pp.204~214 (2013)
- García-Cáceres C, "Role of astrocytes, microglia, and tanycytes in brain control of systemic metabolism", Nat Neurosci, 22, pp.7~14 (2019)
- Bolós M, "Alzheimer’s disease as an inflammatory disease", Biomol Concepts, 18, pp.37~43 (2017)
- Palmer AL, "Astrocytes and aging", Front Aging Neurosci, 10, pp.337~ (2018)
- Syed M. Q. Hussaini, "New Roles for Old Glue: Astrocyte Function in Synaptic Plasticity and Neurological Disorders", International Neurourology Journal, 22, pp.106~114 (2018), 대한배뇨장애요실금학회
- Hartman TK, "Mutant mice with small amounts of BubR1 display accelerated age-related gliosis", Neurobiol Aging, 28, pp.921~927 (2007)
- Cho CH, "sFRP3 inhibition improves age-related cellular changes in BubR1 progeroid mice", Aging Cell, 18, pp.e12899~ (2019)
- Hussaini SM, "Heatinduced antigen retrieval : an effective method to detect and identify progenitor cell types during adult hippocampal neurogenesis", J Vis Exp, 78, pp.50769~ (2013)
- Sofroniew MV, "Astrogliosis", Cold Spring Harb Perspect Biol, 7, pp.a020420~ (2014)
- Hickman S, "Microglia in neurodegeneration", Nat Neurosci, 21, pp.1359~1369 (2018)