Mitochondria in Neuroplasticity, Neurologic Disease and Aging.

Abstract SCI-2

Brain cells are influenced in health and disease by several types of bone marrow-derived cells (BMDC) that either reside in, or are recruited to, the brain. Microglia are macrophage-like cells that continuously surveil the brain, and respond to injury, infection or disease by endocytosing damaged/dead cells and microorganisms, and by producing pro-inflammatory cytokines. Lymphocytes of various phenotypes enter the brain in large numbers in response to acute injury (stroke, severe epileptic seizures, trauma) or chronic disease (multiple sclerosis, Alzheimer's disease). While microglia and lymphocytes are best known for their adverse effects on neuronal function and survival in injury or disease (Arumugam et al., Nat Med. 2006; 12:621-3), recent findings suggest that these cells may also serve important beneficial roles in processes such as learning and memory (Ziv et al. Nat Neurosci. 2006; 9:268-75). Here I describe how BMDC can affect neuronal excitability and mitochondrial function in normal physiological settings and in disease states. We have found that low concentrations of tumor necrosis factor (TNF), which is produced by microglia/macrophages and lymphocytes, can promote neuronal survival and synaptic plasticity by activating the transcription factor NF-kB to induce the expression of glutamate receptor subunits, mitochondrial SOD2 and Bcl2 (Mattson and Meffert, Cell Death Differ. 2006; 13:852-60). When bone marrow from TNF receptor-deficient mice was transplanted into irradiated wild type mice, neurons in the brain were more vulnerable to epileptic seizures, suggesting that TNF suppresses neuronal excitability (Guo et al., Neuromolecular Med. 2004; 5:219-34). In other studies we found that a mutation in presenilin-1 (PS1) that causes early-onset inherited Alzheimer's disease (AD) perturbs lymphocyte signaling (Morgan et al., Neuromolecular Med. 2007; 9:35-45). Splenic T cells isolated from PS1 mutant knockin mice respond poorly to proliferative signals and have downregulated cluster designation 3 and interleukin (IL)- 2-receptor expression necessary for a normal T-cell immune response. The adverse effect of mutant PS1 involves perturbed calcium regulation and cytokine signaling in lymphocytes, and associated sensitivity of lymphocytes to mitochondria-mediated apoptosis. These findings suggest that abnormalities in immune function might play roles in the pathogenesis of AD. Finally, I describe very recent findings that suggest roles for toll-like receptor signaling in learning and memory processes, and in neuronal responses to energy deprivation (Tang et al., Proc Natl Acad Sci U S A. 2007; 104:13798-803). Emerging findings therefore suggest that both innate and humoral signaling from BMDC to neurons play interesting roles in regulating neuronal plasticity and energy metabolism in health and disease.