Long-term evidence has confirmed the involvement of an inflammatory component in neurodegenerative disorders including Alzheimer’s disease (AD). This view is supported, in part, by data suggesting that selected non-steroidal anti-inflammatory drugs (NSAIDs) provide protection. Additionally, molecular players of the innate immune system have recently been proposed to contribute to these diseases. Toll-like receptors (TLRs) are transmembrane pattern-recognition receptors of the innate immune system that recognize different pathogen-derived and tissue damage-related ligands. TLR4 mediated signaling has been reported to contribute to the pathogenesis of age-related neurodegenerative diseases, including AD. Although the pathophysiology of AD is not clear, soluble aggregates (oligomers) of the amyloid β peptide (Aβo) have been proven to be key players in the pathology of AD. Among others, Aβo promote Ca 2+ entry and mitochondrial Ca 2+ overload leading to cell death in neurons. TLR4 has recently been found to be involved in AD but the mechanisms are unclear. Our group recently reported that lipopolysaccharide (LPS), a TLR4 receptor agonist, increases cytosolic Ca 2+ concentration leading to apoptosis. Strikingly, this effect was only observed in long-term cultured primary neurons considered a model of aging neurons, but not in short-term cultured neurons resembling young neurons. These effects were significantly prevented by pharmacological blockade of TLR4 receptor signaling. Moreover, TLR4 expression in rat hippocampal neurons increased significantly in aged neurons in vitro . Therefore, molecular patterns associated with infection and/or brain cell damage may activate TLR4 and Ca 2+ signaling, an effect exacerbated during neuronal aging. Here, we briefly review the data regarding the involvement of TLR4 in AD.

We have studied the effects of glutamate receptor agonists on the cytosolic Ca2+ concentration ([Ca/+]i) of single rat anterior pituitary (AP) cells. Ionotropic (NMDA and kainate/AMPA) and, to a smaller extent, metabotropic glutamate receptors were both present in all the five AP cell types, defined by the hormone they store. Cells within all the types responded also to thyrotropin-releasing hormone (TRH). Alternative typing by the response to four well-established hypothalamic releasing hormones (HRHs), GHRH, GnRH, CRH, and TRH, was performed. One-third of the cells were not sensitive to any HRH, another third were sensitive to only one HRH, and the last third were sensitive to more than one HRH, frequently to all four. Only the cells responding to TRH showed functional glutamate receptors. Superimposed to the above association, the strongest responses to glutamate were found in the cells responsive to multiple HRHs. These results suggest that glutamate may act, by a nonsynaptic mechanism, as a new releasing factor for one or, like TRH, several AP hormones. Coexpression of glutamate and TRH receptors in the subpopulation of cells responsive to multiple HRHs might have a functional meaning, perhaps related to phenotypic plasticity and long-term regulation of hormone secretion by the anterior pituitary.