Remarkably, plaques were almost completely abolished in littermate APP/PS1 mice that lack the NET (NET KO, APP/PS1). Similar results were obtained selleck chemical U0126 with western blots of brain homogenates (Figure ?(Figure1b1b). Figure 1 Enhancing norepinephrine may be a promising strategy to treat Alzheimer’s disease. (a) Plaque deposition in the hippocampus (HP) and cortex (CTX) of 1-year-old APP/PS1 mice (NET WT,APP/PS1) and norepinephrine transporter knockout APP/PS1 mice (NET KO,APP/PS1) … These results suggest that attenuating NET activity can reduce A?? levels, perhaps by increasing phagocytosis or another NE-mediated mechanism described in this review. Interestingly, full-length APP and the C-terminal fragment of APP were also reduced.

The reasons for this are not clear, but raise the possibility that a change in APP production or turnover contributes to the decrease in A?? levels. Consistent with this finding, selective lesion of the ascending noradrenergic bundle with 6-hydroxydopamine in rats increased cortical APP [63]. Combined with the results that atomoxetine + L-DOPS reduces AD-like neuropathology and cognitive deficits in 5xFAD mice [59], these data support the use of NET inhibitors in AD patient populations. While studies using NE pharmacotherapy in AD models show promise for disease treatment, these studies must be interpreted with caution because the effects of noradrenergic drugs are complicated by multiple adrenergic receptor subtypes with different distributions and signaling capabilities.

There are a number of studies that suggest noradrenergic stimulation actually increases certain proinflammatory markers, and that some adrenergic receptor blockade can be therapeutic. Pharmacological activation of ??-adrenergic receptors (especially ??2-adrenergic) increases mRNA and protein levels for IL-1B and 1L-6 in macrophages, microglia Cilengitide and brain parenchyma [64-66]. Administration of adrenergic receptor antagonists in vivo can protect against the inflammatory response induced by a foot shock [67], peripheral bacterial challenge [68] or ischemia [69,70]. Nevibolol, a ??1-blocker, can also reduce amyloid production in TG2576 mice that have established amyloid and cognitive impairment, although it does not improve cognition [71].

One potential explanation for the dual beneficial and harmful effects of adrenergic receptor stimulation is that the loss of LC neurons coupled with the compensatory sprouting by surviving cells probably creates a situation where NE transmission is compromised in some selleck kinase inhibitor brain regions, and overactive in others [6,19-24,28]. Clinical studies of pharmacotherapies that modulate norepinephrine in AD Most clinical studies using noradrenergic pharmacotherapy to date have been primarily focused on treating the aggression and other behavioral disturbances that occur in many late-stage AD patients.