Everyone ages, but only some will develop a neurodegenerative disorder in the process. Disease might occur when cells fail to respond adaptively to age-related increases in oxidative, metabolic and ionic stress, thereby resulting in the accumulation of damaged proteins, DNA and membranes. Determinants of neuronal vulnerability might include cell size and location, metabolism of disease-specific proteins and a repertoire of signal transduction pathways and stress resistance mechanisms. Emerging evidence on protein interaction networks that monitor and respond to the normal ageing process suggests that successful neural ageing is possible for most people, but also cautions that cures for neurodegenerative disorders are unlikely in the near future.

The innate immune system senses the invasion of pathogenic microorganisms and tissue injury through Toll-like receptors (TLR), a mechanism thought to be limited to immune cells. We now report that neurons express several TLRs, and that the levels of TLR2 and -4 are increased in neurons in response to IFN-␥ stimulation and energy deprivation. Neurons from both TLR2 knockout and -4 mutant mice were protected against energy deprivation-induced cell death, which was associated with decreased activation of a proapoptotic signaling cascade involving jun N-terminal kinase and the transcription factor AP-1. TLR2 and -4 expression was increased in cerebral cortical neurons in response to ischemia/reperfusion injury, and the amount of brain damage and neurological deficits caused by a stroke were significantly less in mice deficient in TLR2 or -4 compared with WT control mice. Our findings establish a proapoptotic signaling pathway for TLR2 and -4 in neurons that may render them vulnerable to ischemic death.AP-1 ͉ apoptosis ͉ innate immunity ͉ ischemic stroke ͉ microglia T oll-like receptors (TLRs) are a family of at least 11 proteins that function as key mediators of innate immunity, responding to diverse microbial products and injury-induced endogenous ligands (1). Activation of TLRs initiates signal transduction cascades that involve kinases including atypical forms of protein kinase C and the transcription factors activator protein-1 (AP-1) and NF-B, which induce the expression of genes encoding inflammation-associated molecules and cytokines (2-4). Although TLRs are expressed in leukocytes where their functions have been established, recent findings suggest they can also be expressed in nonimmune cells, including hepatocytes and muscle cells (5,6). TLRs are present in the brain, where their expression is believed to be limited to glial cells (microglia, astrocytes, and oligodentrocytes) (7,8). However, recent findings suggest that neurons may express at least some TLRs responsive to viral RNA or bacterial proteins (9, 10). Ischemic injury to the brain (stroke) is a major cause of morbidity and mortality for which effective treatments are lacking. Studies have shown that TLR2 and -4 are up-regulated in response to ischemia in the kidney and heart, suggesting these two TLRs may play important roles in ischemic tissue injury (11-13). However, neither the specific cells in which TLRs are activated in response to ischemia nor the consequences of TLR signaling for the clinical outcome of an ischemic event have been established. Here we use TLR2 and -4 mutant mice and primary neuronal cell culture and in vivo models of ischemic stroke to elucidate roles for neuronal TLR2 and -4 signaling in the pathogenesis of stroke. Results Neurons Express TLRs and Respond to IFN␥ Stimulation.Previous studies suggested that neurons do not express TLRs (14), whereas others have suggested the presence of TLR3 and -8 in neurons (10). By using multiple technologies, we found that primary mouse cortical neurons express TLR2, -3, and -4. First,...

Mice transgenic for antisense Notch and normal mice treated with inhibitors of the Notch-activating enzyme gamma-secretase showed reduced damage to brain cells and improved functional outcome in a model of focal ischemic stroke. Notch endangers neurons by modulating pathways that increase their vulnerability to apoptosis, and by activating microglial cells and stimulating the infiltration of proinflammatory leukocytes. These findings suggest that Notch signaling may be a therapeutic target for treatment of stroke and related neurodegenerative conditions.