This result was partially confirmed and extended in an independent study with a larger sample population and wider patient demographics. This follow-up study reported a significant www.selleckchem.com/products/Vorinostat-saha.html association between the low-activity variant of DBH alone and AD risk that was mostly attributable to males over the age of 75, and also replicated the interaction between DBH and IL-1A polymorphisms [45]. Interestingly, SNPs that are thought to increase adrenergic signaling have also been linked to a risk for developing AD. Individuals homozygous for the C allele of ADRB1 (the ??1-adrenergic receptor) and the the T allele of GNB3 (the G protein ??3 subunit gene), which are associated with increased cAMP levels and mitogen-activated protein kinase activation, have an increased risk for AD [46].

A Chinese case-control study found that a ??2-adrenergic receptor polymorphism which enhances responsiveness is also associated with the risk of sporadic late-onset AD [47]. These studies highlight the complicated nature of noradrenergic signaling in AD; activation of some receptor subtypes may suppress neuroinflammation and neuropathology, while other receptors may exacerbate aspects of the disease. Recent biomarker studies in living subjects have also confirmed a proinflammatory state in AD [48-51]. Of note, increased proinflammatory and decreased anti-inflammatory markers account for the majority of changes detectable in a large panel of cerebrospinal fluid analytes in MCI and AD [49,50]. By promoting proinflammatory responses, suppressing anti-inflammatory responses and impairing A?? degradation and clearance, LC degeneration and NE loss can therefore be considered a triple threat to AD pathogenesis.

Treatments that increase norepinephrine in AD animal models ameliorate AD-like pathology and cognitive decline In vitro and animal studies have provided the most compelling evidence that increasing NE could have beneficial effects on both AD neuropathology and cognitive symptoms. In vitro challenge of human acute monocytic leukemia cells (THP-1) with A??42 induced cytotoxicity and provoked a neuroinflammatory response that was dose-dependently attenuated by NE [52]. Treatment with cAMP or forskolin, a protein kinase A activator, had similar effects, suggesting that NE’s protective effects were regulated, at least in part, via stimulation of ??-adrenergic receptors and the corresponding activation of the cAMP/protein kinase A signaling pathway [52].

Another in vitro study in hNT neuronal and primary hippocampal cultures revealed a neuroprotective effect of NE against both A??42- and A??25-35-induced increases in oxidative stress, mitochondrial dysfunction and cell death [53]. The neuroprotective effects Batimastat were mediated by activation of ??-adrenoceptor/cAMP signaling and also required the brain-derived neurotrophic factor/tropo myosin-related kinase B pathway, although some ??-receptor-independent effects of http://www.selleckchem.com/products/FTY720.html NE persisted [53].