Elsevier

Brain Research

Volume 1702, 1 January 2019, Pages 46-53
Brain Research

Research report
Amyloid beta peptides, locus coeruleus-norepinephrine system and dense core vesicles

https://doi.org/10.1016/j.brainres.2018.03.009Get rights and content

Highlights

  • ā€¢

    Several peptidergic systems converge onto the LC to counteract responsivity to stress.

  • ā€¢

    The LC may be a critical site of interaction of chromogranin peptides, NE and AĪ².

  • ā€¢

    DCV may play an important role in preserving the integrity of the LC-NE system under conditions of stress.

  • ā€¢

    Dysregulation of DCV and the chromogranin peptides they harbor, may have deleterious effects on the LC.

Abstract

The evolution of peptidergic signaling systems in the central nervous system serves a distinct and crucial role in brain processes and function. The diversity of physiological peptides and the complexity of their regulation and secretion from the dense core vesicles (DCV) throughout the brain is a topic greatly in need of investigation, though recent years have shed light on cellular and molecular mechanisms that are summarized in this review. Here, we focus on the convergence of peptidergic systems onto the Locus Coeruleus (LC), the sole provider of norepinephrine (NE) to the cortex and hippocampus, via large DCV. As the LC-NE system is one of the first regions of the brain to undergo degeneration in Alzheimerā€™s Disease (AD), and markers of DCV have consistently been demonstrated to have biomarker potential for AD progression, here we summarize the current literature linking the LC-NE system with DCV dysregulation and AĪ² peptides. We also include neuroanatomical data suggesting that the building blocks of senile plaques, AĪ² monomers, may be localized to DCV of the LC and noradrenergic axon terminals of the prefrontal cortex. Finally, we explore the putative consequences of chronic stress on AĪ² production and the role that DCV may play in LC degeneration. Clinical data of immunological markers of DCV in AD patients are discussed.

Introduction

The brain has evolved to support two modes of communication: fast acting neurotransmitters and slow acting neuropeptides. The packaging of these diverse signaling molecules into separate secretory compartments of the cell enables an effective means of regulating their exocytosis independently (Zhang et al., 2011). Thus, small clear synaptic vesicles (SV) generally contain low molecular weight neurotransmitters, while neuropeptides are packaged in large dense core vesicles (DCV). Neurotransmitters stored in SVs are primed for fast, phasic release at active zones of the nerve terminal upon depolarization (Wang, 2008). Once released into the synaptic cleft, a signal is rapidly transduced via binding of post synaptic receptors and terminated via the degradation or re-uptake of transmitter, clearing the synaptic cleft. In contrast, the second mode of communication, via neuropeptide transmitters, is a slower and long lasting mode of communication that is not spatially or temporally confined, based on their release from separate asynaptic sites and their long half lives (Ludwig and Leng, 2006). Thus, while fast acting neurotransmitters provide the brain with massive computational power, spatial and temporal precision, slow acting neuropeptides have broad reaching, long lasting affects that ultimately pass signals between subpopulations of neurons. Thus, the brain is equip with two parallel modes of communication, that are qualitatively different in their outcome. Persistent neuropeptide activity is thought to modulate behavioral states, as the system is designed to initiate global changes in the brain state by diffusing from one population of cells to another (Ludwig and Leng, 2006).

The Locus Coeruleus (LC)-Norepinephrine (NE) system is poised to participate in this broad reaching modulatory signaling, as norepinephrine is amongst the prominent catecholamine neurotransmitters known to be stored and undergo co-transmission with neuropeptides from large DCV. The LC is a cluster of noradrenergic neurons located at the base of the fourth ventricle that are recognized as the sole provider of NE to the frontal cortex and hippocampus, and whose broad reaching afferents provide NE to the entire neuraxis. The LC-NE system is critically involved in promoting attention, wakefulness and cognition upon receiving input from hypocretin (orexin) neurons of the hypothalamus (Berridge and Waterhouse, 2003). It is also responsive to the neurohormone Corticotropin Releasing Factor (CRF) during both acute and chronic stressors, both cognitive and physical (Van Bockstaele et al., 1996, Van Bockstaele et al., 1998, Valentino and Van Bockstaele, 2008). The Central Nucleus of the Amygdala (CeA) is a critical source of CRF that can impact on LC activity via effects on dendrites in the rostrolateral peri-coerulear region (Van Bockstaele et al., 1998), thus may serve as a cellular substrate for modulation of brain noradrenergic activity and may serve as a mechanism for the integration of emotional and cognitive responses to stress (Van Bockstaele et al., 1998, Valentino and Van Bockstaele, 2008). Additionally, the LC receives input from a variety of neuropeptides residing in DCVs, and is a point of convergence for multiple peptidergic systems in modulating responsivity to stress.

Recently, the locus-coeruleus (LC)-norepinephrine (NE) system has been identified as an underappreciated and understudied circuit in the context of AD (Ross et al., 2015). The finding that dense core vesicle specific markers are dysregulated in AD, and that the LC is amongst the earliest regions to undergo degeneration, brings to light an important question regarding the role of DCV dysregulation in LC-NE system dysfunction, and the potential role of DCVs in degenerative conditions of catecholaminergic neurons. In this review, we will start by synthesizing recent and previous research regarding DCV and neuropeptide storage and release, then move into current literature on the impact of neuropeptide transmission on the integrity and responsivity of the LC-NE system, and finally, review clinical evidence that dense core vesicle markers may play a role in neurodegenerative disease states, particularly in catecholamine neuronal populations.

Section snippets

Neuropeptide storage and release

Neuropeptides are synthesized in the cell body and condensed into DCV (Wang 2008). DCV can be released in the soma as well as in the nerve terminal far away from active zones. Formation of DCVs is a multi-step process that involves the sorting of DCV cargo into immature secretory granules in the trans golgi network (TGN) (Aixa Alfonso, 2010). These immature granules do not yet contain a dense core and are not stimulus-responsive. Subsequently, immature vesicles may be remodeled to form mature

Regulation of locus coeruleus-NE system: Peptidergic convergence and DCV

Physiologically, the LC is poised to switch between two modes of discharge activity that dictate behavioral outcomes in response to task- and stress- related stimuli [for extensive review see (Aston-Jones and Cohen, 2005, Valentino and Van Bockstaele, 2008). The LC tonic discharge rate is related to task-focused states and states of arousal. During passive, or unstressed conditions, the LC exhibits low levels of tonic discharge that are associated with decreased attention to task related

Endogenous amyloid beta production and putative physiological function

AĪ² has been recognized as an endogenous neuropeptide that undergoes physiological metabolism in the central nervous system for over a decade and we still lack a basic understanding of its physiological function. Early studies demonstrating the existence of endogenous 4ā€ÆkDa AĪ² peptides, identical to those deposited as extracellular plaques in Alzheimerā€™s disease (AD), were conducted in human mononuclear leukemic and neuroblastoma (M17) cell lines (Shoji et al., 1992). In the same year,

Amyloid beta peptides, norepinephrine and dense core vesicles: Significance for LC autoregulation

While it has yet to be investigated in vivo, APP, Ī²- and Ī³- secretases have been localized to neuron-like chromaffin cells in vitro (Toneff et al., 2013). Further, this important study demonstrated that under conditions of KCl induced depolarization or forskolin treatment, AĪ² peptides underwent regulated co-secretion with other peptides and catecholamine neurotransmitters. Amongst co-secreted neuropeptides were galanin, enkephalin, NPY and catecholamine neurotransmitters including dopamine,

Implications for disease: Chromogranin peptides in AD

Synapse loss is the best correlate for cognitive impairment observed in AD (Terry et al., 1991). CgA, SGI, and SGII are well known markers of large DCV, and have recently been identified amongst many synaptic proteins, as biomarkers of AD (Davis et al., 1999, Jahn et al., 2011, Wildsmith et al., 2014). A number of investigators have used alterations in synaptic protein levels and their relationship with AĪ² plaques to identify vulnerable subpopulations of neurons in cognitive deficits observed

Conclusions

Taken together, the studies described here suggest that DCV may play an important role in preserving the integrity of the LC-NE system under conditions of stress, and that under the degenerative conditions of AD, the dysregulation of DCV and the chromogranin peptides they harbor, may have deleterious effects on the LC. This may result in decreased adaptive responses to stress, thus explaining, in part, increased indices of stress responsivity in AD patient populations. Alternatively, LC

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