NE has several strong influences on microglial function, and in general suppresses the production of proinflammatory cytokines and promotes the production of anti-inflammatory molecules. Thus, it is not surprising sellekchem that dsp-4 treatment also exacerbates the neuroinflammatory response in multiple brain regions of APP/PS1 mice [36,37]. Interestingly, a recent study reported that in addition to increased A?? deposition, dsp-4 lesions of the LC in APP/PS1 mice also resulted in olfactory deficits, another common and early pathology seen in AD patients [38]. Among the questions raised by these findings, an important issue with therapeutic implications is whether the effects of LC lesions in AD mouse models are due solely to the loss of NE itself, the loss of co-transmitters in LC neurons, collateral damage from the neuro degenerative process itself, or some combination thereof.

To help resolve these issues, we recently crossed APP/PS1 mice with dopamine ??-hydroxylase knockout (DBH-/-) mice that lack the ability to synthesize NE but have intact LC neurons [39]. While APP/PS1 and DBH-/- single-mutant mice each displayed moderate hippocampal long-term potentiation (LTP) and spatial memory impairments, the two mutations had an additive effect, resulting in double mutants with severely compromised LTP and maze performance. Somewhat surprisingly, the genetic loss of NE had no apparent effect on AD-like neuropathology in the double mutant. Nondegenerative loss of NE produced by Ear2 knockout, which prevents the development of most LC neurons, also exacerbated LTP and memory deficits but had no effect on plaque deposition in APP/PS1 mice.

However, dsp-4 worsened neuropathology in the APP/PS1, DBH-/- double mutant. Combined, these results indicate that the LC neuronal loss contributes to distinct aspects of AD; loss of NE itself impairs synaptic plasticity and cognitive performance, while the physical process of LC neuron degeneration Dacomitinib exacerbates during AD-like neuropathology. In summary, combining expression of familial AD mutations with LC lesions or NE deficiency appears to more closely recapitulate the neuropathological and cognitive symptoms of AD compared with mutant APP expression alone, and implicates LC loss as a crucial component of AD. Neuroinflammation is a key mechanism linking loss of locus coeruleus neurons and norepinephrine innervation with AD Recent studies provide insights into the mechanisms by which LC dysfunction and NE loss facilitate AD pathogenesis. There is growing evidence suggesting that the inflammatory response induced and/or augmented by LC degeneration is a key mechanism contributing to the initiation and progression of AD pathogenesis.