ABSTRACT
Exercise is a treatment paradigm that can ameliorate cognitive dysfunction in Alzheimer disease (AD) and AD mouse models. Since exercise is also known to alter the peripheral immune response, one potential mechanism for the cognitive improvement following exercise may be by modulating the inflammatory repertoire in the central nervous system. We investigated the effects of voluntary exercise in the Tg2576 mouse model of AD at a time-point at which pathology has already developed. Inflammatory mRNA markers are increased in sedentary Tg2576 mice versus non-transgenic controls. We demonstrate that short-term voluntary wheel running improved spatial learning in aged transgenic mice as compared to sedentary Tg2576 controls. Inflammatory profiles of the Tg2576 and non-transgenic mice were different following exercise with the non-transgenic mice showing a broader response as compared to the Tg2576. Notably, exercising Tg2576 exhibited increases in a few markers including CXCL1 and CXCL12, two chemokines that may affect cognition.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Cognition/physiology , Inflammation/rehabilitation , Aging , Alzheimer Disease/complications , Alzheimer Disease/genetics , Alzheimer Disease/rehabilitation , Animals , Behavior, Animal , Chemokine CXCL1/genetics , Chemokine CXCL1/metabolism , Chemokine CXCL2/genetics , Chemokine CXCL2/metabolism , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay/methods , Gene Expression Regulation/physiology , Inflammation/etiology , Maze Learning/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Microarray Analysis , RNA, Messenger/metabolism , Time FactorsABSTRACT
Frontotemporal dementia (FTD) is a neurodegenerative disease associated with aging for which the etiology is unclear. Relatively little is known about the pathology of this disease, which has only recently been a topic of investigation for dementia researchers. Though the known pathology of FTD includes neuron loss, the mechanism of neuronal death is not known. In this study, the authors investigated apoptotic pathways as a possible mechanism of neuronal cell death in FTD. They evaluated immunoreactivity for Bcl-2 family protein members Bcl-x and Bax in postmortem frontal cortex from FTD, AD, and control cases. Bcl-x(L), Bcl-x(S), and Bax all exhibited altered immunoreactivity in FTD cases as compared with control cases. Bcl-x immunoreactivity varied widely among both controls and FTD cases. However, Bcl-x(L) showed strong white matter immunoreactivity in all FTD cases, whereas white matter immunoreactivity was absent in controls. These trends in Bcl-x immunoreactivity suggest a strong white matter involvement in the pathology of FTD. Bax immunoreactivity also varied across all cases. Bax immunoreactivity was observed in terminal transferase dUTP nick ending labeling (TUNEL) positive neurons in both FTD and AD cases. However, one notable finding was immunoreactivity to Bax in astrocytes of FTD cases, as well as endothelial cells of the cerebrovasculature. Neither astrocytic nor endothelial cell immunoreactivity to Bax was exhibited in control or AD cases. Because Bax is a pro-apoptotic protein, this finding suggests the presence of a cerebrovascular component in the pathology of FTD. These findings, coupled with the proposed functions of the Bcl-2 family proteins, suggest that an apoptotic pathway may be responsible for neuron, and possibly astrocyte, death in FTD.
Subject(s)
Cerebral Cortex/metabolism , Dementia/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Aged , Aged, 80 and over , Astrocytes/metabolism , Astrocytes/pathology , Cerebral Cortex/blood supply , Cerebral Cortex/pathology , Dementia/pathology , Humans , Middle Aged , Neurons/metabolism , Neurons/pathology , bcl-X ProteinABSTRACT
Frontotemporal dementia (FTD) is a neurodegenerative disease which affects mainly the frontal and anterior temporal cortex. It is associated with neuronal loss, gliosis, and microvacuolation of lamina I to III in these brain regions. In previous studies we have described neurons with DNA damage in the absence of tangle formation and suggested this may result in tangle-independent mechanisms of neurodegeneration in the AD brain. In the present study, we sought to examine DNA fragmentation and activated caspase-3 expression in FTD brain where tangle formation is largely absent. The results demonstrate that numerous nuclei were TdT positive in all FTD brains examined. Activated caspase-3 immunoreactivity was detected in both neurons and astrocytes and was elevated in FTD cases as compared to control cases. A subset of activated caspase-3-positive cells were also TdT positive. In addition, the cell bodies of a subset of astrocytes showed enlarged, irregular shapes, and vacuolation and their processes appeared fragmented. These degenerating astrocytes were positive for activated caspase-3 and colocalized with robust TdT-labeled nuclei. These findings suggest that a subset of astrocytes exhibit degeneration and that DNA damage and activated caspase-3 may contribute to neuronal cell death and astrocyte degeneration in the FTD brain. Our results suggest that apoptosis may be a mechanism of neuronal cell death in FTD as well as in AD (228).
