Chronically active: activation of microglial proteolysis in ageing and neurodegeneration

Stolzing, Alexandra; Sethe, Sebastian; Grune, Tilman

doi:10.1179/135100005x70198

Cited by 11 publications

(9 citation statements)

References 61 publications

(66 reference statements)

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“…These results suggest that there might be regional differences in microglial activation in the aged brain. The increase in number of activated microglia with age has been reported in many human and animal studies (Conde and Streit, 2006, Felzien, et al, 2001, Sheffield and Berman, 1998), and chronic activation of microglia in the aging brain has been linked with increased neuronal loss (Stolzing, et al, 2005). In addition, microglia from the aging brain show an altered phenotype that is considered dysfunctional, associated with the loss of neuroprotective properties that likely contributes to age-related neurodegeneration (Streit, et al, 2004).…”

Section: Discussionmentioning

confidence: 97%

Exacerbated glial response in the aged mouse hippocampus following controlled cortical impact injury

Sandhir

Onyszchuk

Berman

2008

Experimental Neurology

166

133

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Old age is associated with enhanced susceptibility to and poor recovery from brain injury. An exacerbated microglial and astrocyte response to brain injury might be involved in poor outcomes observed in the elderly. The present study was therefore designed to quantitate the expression of markers of microglia and astrocyte activation using real-time RT-PCR, immunoblot and immunohistochemical analysis in aging brain in response to brain injury. We examined the hippocampus, a region that undergoes secondary neuron death, in aged (21-24 month) and adult (5-6 month) mice following controlled cortical impact (CCI) injury to the sensorimotor cortex. Basal mRNA expression of CD11b and Iba1, markers of activated microglia, was higher in aged hippocampus as compared to the adult. The mRNA expression of microglial markers increased and reached maximum 3 days post injury in both adult and aged mice, but was higher in the aged mice at all time points studied, and in the aged mice the return to baseline levels was delayed. Basal mRNA expression of GFAP and S100B, markers of activated astrocytes, was higher in aged mice. Both markers increased and reached maximum 7 days post injury. The mRNA expression of astrocyte markers returned to near basal levels rapidly after injury in the adult mice, whereas again in the aged mice return to baseline was delayed. Immunochemical analysis using Iba1 and GFAP antibodies indicate accentuated glial responses in the aged hippocampus after injury. The pronounced and prolonged activation of microglia and astrocytes in hippocampus may contribute to worse cognitive outcomes in the elderly following TBI.

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Section: Discussionmentioning

confidence: 97%

Exacerbated glial response in the aged mouse hippocampus following controlled cortical impact injury

Sandhir

Onyszchuk

Berman

2008

Experimental Neurology

166

133

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“…However, we also observe an age‐associated decrease in proteasomal activity. Declining antioxidative defence enzyme activities with no increase in 20S proteasome activity to cope with increasing levels of oxidized protein lead to a damage cascade (Merker et al ., 2001; Stolzing et al ., 2005). It is known that ROS and NO generation increases in other tissues, such as bone marrow, with age and this may play a contributory role in damage accumulation by MPC.…”

Section: Discussionmentioning

confidence: 99%

Age‐related impairment of mesenchymal progenitor cell function

Stolzing¹,

2006

Self Cite

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SummaryIn most mesenchymal tissues a subcompartment of multipotent progenitor cells is responsible for the maintenance and repair of the tissue following trauma. With increasing age, the ability of tissues to repair themselves is diminished, which may be due to reduced functional capacity of the progenitor cells. The purpose of this study was to investigate the effect of aging on rat mesenchymal progenitor cells. Mesenchymal progenitor cells were isolated from Wistar rats aged 3, 7, 12 and 56 weeks. Viability, capacity for differentiation and cellular aging were examined. Cells from the oldest group accumulated raised levels of oxidized proteins and lipids and showed decreased levels of antioxidative enzyme activity. This was reflected in decreased fibroblast colony-forming unit (CFU-f) numbers, increased levels of apoptosis and reduced proliferation and potential for differentiation. These data suggest that the reduced ability to maintain mesenchymal tissue homeostasis in aged mammals is not purely due to a decline in progenitor cells numbers but also to a loss of progenitor functionality due to the accumulation of oxidative damage, which may in turn be a causative factor in a number of age-related pathologies such as arthritis, tendinosis and osteoporosis.

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“…Furthermore, pharmacological manipulations indicate that NAADP is a likely candidate for regulating Ca 2+ signaling in astrocytes (Singaravelu and Deitmer, 2006). It is unclear whether this source of Ca 2+ regulation is altered by aging; however, the aging brain is characterized by increased lysosomal markers and decreased lysosomal function (Lynch and Bi, 2003; Keller et al, 2004; Stolzing et al, 2005). Thus, the role of this source of Ca 2+ in susceptibility to Ca 2+ dysregulation should be examined in the future.…”

Section: Intracellular Ca2+ Storesmentioning

confidence: 99%

Susceptibility to calcium dysregulation during brain aging

Kumar

Bodhinathan

Foster

2009

Front. Ag. Neurosci.

110

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Calcium (Ca2+) is a highly versatile intracellular signaling molecule that is essential for regulating a variety of cellular and physiological processes ranging from fertilization to programmed cell death. Research has provided ample evidence that brain aging is associated with altered Ca2+ homeostasis. Much of the work has focused on the hippocampus, a brain region critically involved in learning and memory, which is particularly susceptible to dysfunction during senescence. The current review takes a broader perspective, assessing age-related changes in Ca2+ sources, Ca2+ sequestration, and Ca2+ binding proteins throughout the nervous system. The nature of altered Ca2+ homeostasis is cell specific and may represent a deficit or a compensatory mechanism, producing complex patterns of impaired cellular function. Incorporating the knowledge of the complexity of age-related alterations in Ca2+ homeostasis will positively shape the development of highly effective therapeutics to treat brain disorders.

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Chronically active: activation of microglial proteolysis in ageing and neurodegeneration

Cited by 11 publications

References 61 publications

Exacerbated glial response in the aged mouse hippocampus following controlled cortical impact injury

Exacerbated glial response in the aged mouse hippocampus following controlled cortical impact injury

Age‐related impairment of mesenchymal progenitor cell function

Susceptibility to calcium dysregulation during brain aging

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