Cell-autonomous role of Presenilin in age-dependent survival of cortical interneurons

AUTHORS

Jongkyun Kang, Jie Shen

ABSTRACT

Mutations in the PSEN1 and PSEN2 genes are the major cause of familial Alzheimer’s disease. Previous studies demonstrated that Presenilin (PS), the catalytic subunit of γ-secretase, is required for survival of excitatory neurons in the cerebral cortex during aging. However, the role of PS in inhibitory interneurons had not been explored.

To determine PS function in GABAergic neurons, we generated inhibitory neuron-specific PS conditional double knockout (IN-PS cDKO) mice, in which PS is selectively inactivated by Cre recombinase expressed under the control of the endogenous GAD2 promoter. We then performed behavioral, biochemical, and histological analyses to evaluate the consequences of selective PS inactivation in inhibitory neurons.

IN-PS cDKO mice exhibit earlier mortality and lower body weight despite normal food intake and basal activity. Western analysis of protein lysates from various brain sub-regions of IN-PS cDKO mice showed significant reduction of PS1 levels and dramatic accumulation of γ-secretase substrates. Interestingly, IN-PS cDKO mice develop age-dependent loss of GABAergic neurons, as shown by normal number of GAD67-immunoreactive interneurons in the cerebral cortex at 2–3 months of age but reduced number of cortical interneurons at 9 months. Moreover, age-dependent reduction of Parvalbumin- and Somatostatin-immunoreactive interneurons is more pronounced in the neocortex and hippocampus of IN-PS cDKO mice. Consistent with these findings, the number of apoptotic cells is elevated in the cerebral cortex of IN-PS cDKO mice, and the enhanced apoptosis is due to dramatic increases of apoptotic interneurons, whereas the number of apoptotic excitatory neurons is unaffected. Furthermore, progressive loss of interneurons in the cerebral cortex of IN-PS cDKO mice is accompanied with astrogliosis and microgliosis.

Our results together support a cell-autonomous role of PS in the survival of cortical interneurons during aging. Together with earlier studies, these findings demonstrate a universal, essential requirement of PS in the survival of both excitatory and inhibitory neurons during aging.

Ultrastructural effects of nerve growth factor and betamethasone on nerve regeneration after experimental nerve injury

AUTHORS

Leman Sencar, Mustafa Güven, Dilek Şaker, Tuğçe Sapmaz, Abdullah Tuli, and Sait Polat

ABSTRACT

Peripheral nerve injuries (PNI) are an important health problem in the world. In this study, the effects of nerve growth factor (NGF) and betamethasone on nerve regeneration after sciatic nerve crush injury were examined by footprint analysis, electron microscopic, histomorphometric, and biochemical methods. Fifty Wistar rats were divided into five groups as intact control, experimental control, NGF, betamethasone, and NGF+betamethasone combined treatment groups. After the injury, betamethasone was subcutaneously injected into the lesion area of the treatment groups three times during the first day. NGF was subcutaneously injected into the lesion area of treatment groups for 14 days. Footprint analysis was made on 7, 14, 21, 28, and 35 days and after 6 weeks, tissue samples were obtained from all groups. In the experimental control group, there were severe degenerative changes in most of the axons and myelin sheaths of the nerve fibers. Moreover, an increase of MDA levels and a decrease in SOD activities were found in this group. On the other hand, malondialdehyde (MDA) levels decreased, superoxide dismutase (SOD) activities increased and significant motor functional recovery were found in the combined treatment group. The number of axons, axon diameters, and myelin thickness were significantly greater in the combined treatment group when compared with experimental control and other treatment groups. It was thought that nerve regenerative effects of NGF and anti-inflammatory and/or anti-edematous effects of betamethasone could induce functional recovery in the combined treatment group. In conclusion, combined therapy of NGF and betamethasone may be an effective approach for the treatment of PNI.

Natural killer cells activated through NKG2D mediate lung ischemia-reperfusion injury

AUTHORS

Daniel R. Calabrese, Emily Aminian, Benat Mallavia, Fengchun Liu, Simon J. Cleary, Oscar A. Aguilar, Ping Wang, Jonathan Hoover, Jonathan P. Singer, Steven R. Hays, Jeffrey A. Golden, Jasleen Kukreja, Daniel T. Dugger, Mary Nakamura, Lewis L. Lanier, Mark R. Looney, and John R. Greenland

ABSTRACT

Pulmonary ischemia-reperfusion injury (IRI) is a clinical syndrome of acute lung injury that occurs after lung transplantation or remote organ ischemia. IRI causes early mortality and has no effective therapies. While natural killer (NK) cells are innate lymphocytes capable of recognizing injured cells, their roles in acute lung injury are incompletely understood. Here, we demonstrated that NK cells were increased in frequency and cytotoxicity in two different IRI mouse models. We showed that NK cells trafficked to the lung tissue from peripheral reservoirs and were more mature within lung tissue. Acute lung ischemia-reperfusion injury was blunted in a NK cell-deficient mouse strain but restored with adoptive transfer of NK cells. Mechanistically, NK cell NKG2D receptor ligands were induced on lung endothelial and epithelial cells following IRI, and antibody-mediated NK cell depletion or NKG2D stress receptor blockade abrogated acute lung injury. In human lung tissue, NK cells were increased at sites of ischemia-reperfusion injury and activated NK cells were increased in prospectively collected human bronchoalveolar lavage in subjects with severe IRI. These data support a causal role for recipient peripheral NK cells in pulmonary IRI via NK cell NKG2D receptor ligation. Therapies targeting NK cells may hold promise in acute lung injury.