The role of norepinephrine in modulating amyloid beta peptides: implications for neurodegenerative and psychiatric disease

Jennifer Ann Ross

doi:10.17918/D8DH3F

Norepinephrine (NE) exerts a global influence on brain function, from modulating local neuro-inflammatory responses to facilitating large-scale, task-related behaviors. Targeting the brain NE system has proven to be a powerful tool for the treatment of stress-related psychiatric diseases such as depression and anxiety. The ability of NE to influence these highly complex disorders is at least in part due to its role in mediating the central stress response, whose dysregulation results in hyper-arousal, mood-disorders, and a number of other chronic systemic diseases. Stress is also a risk factor for developing Alzheimer's Disease (AD) and emerging evidence suggests an important role of NE in the etiology and progression of AD. Amplification of the stress system disrupts cellular and molecular processes at the synapse, promoting the production and secretion of A[beta]42 peptides and numerous studies indicate that NE can exert profound effects on the production and clearance of A[beta]42 peptides. Thus, the dysregulation of NE under conditions of chronic stress, psychiatric disease, or LC degeneration may directly contribute to an aberrant increase in A[beta]42, suggesting that targeting the NE system may be a novel approach to modulating A[beta]42 levels in early stages of AD to slow or halt the progression of disease. To investigate the subcellular relationship between NE and A[beta], neuroanatomical studies were conducted in the locus coeruleus (LC)- medial prefrontal cortex (mPFC) pathway to determine the distribution of endogenous monomeric A[beta]42 peptides with respect to NE neurons. A42 levels were then measured in two murine models that underwent depletion of NE. Results showed that A[beta]42 was localized to the LC and mPFC of male and female rats. NE depletion reduced A42 levels in both models, an effect potentially mediated by the 2-adrenergic receptor (AR). To better understand the link between NE, chronic stress and aberrant A42 accumulation, we used mice that conditionally overexpress corticotropin releasing factor (CRF OE) to determine if perturbation of the stress-signaling axis would alter A[beta]42 levels or distribution. While overall levels of A42 were not significantly different, we observed a redistribution of A[beta]42 in the LC of male and female CRF OE mice such that significant increases in frequency of co-localization of NE markers and A[beta]42 immunolabeling were observed by immunoelectron microscopy. Results of this research indicate that dysregulation of the LC-mPFC circuit via chronic stress may initiate reversible mechanisms of degeneration. With time, in mid-life, it would be expected that the severity of these alterations would increase given that mechanisms of neuronal resilience decline naturally with age. Therefore targeting the LC-NE system in early stages of AD may have significant therapeutic potential in altering the progression of the disease.

The role of norepinephrine in modulating amyloid beta peptides: implications for neurodegenerative and psychiatric disease

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The role of norepinephrine in modulating amyloid beta peptides: implications for neurodegenerative and psychiatric disease

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