Research reportAmyloid beta peptides, locus coeruleus-norepinephrine system and dense core vesicles
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 4āÆkDa AĪ² peptides, identical to those deposited as extracellular plaques in Alzheimerās 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
References (97)
- et al.
The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes
Brain Res. Brain Res. Rev.
(2003) - et al.
Synaptophysin and chromogranin A immunoreactivities in senile plaques of Alzheimer's disease
Brain Res.
(1991) - et al.
Alpha2A- but not alpha2B/C-adrenoceptors modulate noradrenaline release in rat locus coeruleus: voltammetric data
Eur. J. Pharmacol.
(1999) - et al.
Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo
Neuron
(2008) - et al.
Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo
Neuron
(2005) - et al.
Noradrenergic axon terminals in the cerebral cortex of rat. III. Topometric ultrastructural analysis
Brain Res.
(1977) - et al.
Targeting the Neuropeptide Y System in Stress-related Psychiatric Disorders
Neurobiol. Stress
(2015) - et al.
Noradrenergic regulation of inflammatory gene expression in brain
Neurochem. Int.
(2002) - et al.
Multiple neuropeptides derived from a common precursor are differentially packaged and transported
Cell
(1988) - et al.
The primary structure of human secretogranin II, a widespread tyrosine-sulfated secretory granule protein that exhibits low pH- and calcium-induced aggregation
J. Biol. Chem.
(1989)
Corticotropin-releasing factor and neuropeptide Y: role in emotional integration
Trends Neurosci.
Neuropeptidesāan overview
Neuropharmacology
The granin (chromogranin/secretogranin) family
Trends Biochem. Sci.
APP processing and synaptic function
Neuron
The neurocircuitry and receptor subtypes mediating anxiolytic-like effects of neuropeptide Y
Neurosci. Biobehav. Rev.
Chromogranin A, an āon/offā switch controlling dense-core secretory granule biogenesis
Cell
The intracellular domain of the low density lipoprotein receptor-related protein modulates transactivation mediated by amyloid precursor protein and Fe65
J. Biol. Chem.
Synaptic pathology in Alzheimer's disease: immunological data for markers of synaptic and large dense-core vesicles
Neuroscience
Chromogranin peptides in Alzheimer's disease
Exp. Gerontol.
Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake
Neuron
Prothyrotropin-releasing hormone targets its processing products to different vesicles of the secretory pathway
J. Biol. Chem.
Evidence for nonsynaptic serotonergic and noradrenergic innervation of the rat dorsal horn and possible involvement of neuron-glia interactions
Neuroscience
Locus Coeruleus, norepinephrine and Abeta peptides in Alzheimer's disease
Neurobiol. Stress
Interactions between NPY and CRF in the amygdala to regulate emotionality
Neuropeptides
Beta-amyloid peptides undergo regulated co-secretion with neuropeptide and catecholamine neurotransmitters
Peptides
Convergent regulation of locus coeruleus activity as an adaptive response to stress
Eur. J. Pharmacol.
Amyloid beta peptide-(1ā42) induces internalization and degradation of beta2 adrenergic receptors in prefrontal cortical neurons
J. Biol. Chem.
Characterization of alpha 2-adrenoceptors which increase potassium conductance in rat locus coeruleus neurones
Neuroscience
The molecular function of adrenal chromaffin granules: established facts and unresolved topics
Neuroscience
The chromogranins A and B: the first 25 years and future perspectives
Neuroscience
Regulated formation of Golgi secretory vesicles containing Alzheimer beta-amyloid precursor protein
J. Biol. Chem.
Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses
Nat. Neurosci.
Cellular and subcellular sites for noradrenergic action in the monkey dorsolateral prefrontal cortex as revealed by the immunocytochemical localization of noradrenergic receptors and axons
Cereb. Cortex
Noradrenergic modulation of the prefrontal cortex as revealed by electron microscopic immunocytochemistry
Adv. Pharmacol.
Adaptive gain and the role of the locus coeruleus-norepinephrine system in optimal performance
J. Comp. Neurol.
Peptide secretion: what do we know?
FASEB J.
The locus ceruleus norepinephrine system: functional organization and potential clinical significance
Neurology
Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells
Proc. Natl. Acad. Sci. USA
Spatiotemporal interaction of alpha(2) autoreceptors and noradrenaline transporters in the rat locus coeruleus: implications for volume transmission
J. Neurochem.
The adrenal chromaffin cell
Sci. Am.
Neuropeptide abnormalities in patients with early Alzheimer disease
Arch. Gen. Psychiatry
Control of secretion by temporal patterns of action potentials in adrenal chromaffin cells
J. Neurosci.
Relevance of neuropeptide Y (NPY) in psychiatry
Curr. Top. Med. Chem.
Causes, consequences, and cures for neuroinflammation mediated via the locus coeruleus: noradrenergic signaling system
J. Neurochem.
Chromogranin C: a third component of the acidic proteins in chromaffin granules
J. Neurochem.
Chromogranins A, B, and C: widespread constituents of secretory vesicles
Ann. N Y Acad. Sci.
Isolation and characterization of chromogranins A, B, and C from bovine chromaffin granules and a rat pheochromocytoma
J. Neurochem.
Cited by (9)
The Locus Coeruleus ā Noradrenaline system: Looking into Alzheimer's therapeutics with rose coloured glasses
2022, Biomedicine and PharmacotherapyCitation Excerpt :As a result, NMDA receptors identify the simultaneous action of pre- as well as post-synaptic neuronal cells. One intriguing feature of neuronal cells in LC is that the duration as well as characteristics of soma release of NA, exhibit greater release duration, greater action potential frequency and may take place via dense core vesicular neuropeptide structures, as compared to those that affect NA release from the terminal regions [136,137]. Thereby, the local Ī±2A auto-receptors are activated, in response to this slow release, which shall hinder the LC action and retard NA release in neocortical region [138].
Noradrenaline in the aging brain: Promoting cognitive reserve or accelerating Alzheimer's disease?
2021, Seminars in Cell and Developmental BiologyCitation Excerpt :Thus, NMDA receptors detect the coincident activity of pre- and postsynaptic neurons. One interesting property of LC neurons is that the timing and factors that influence release of noradrenaline from the soma versus from varicosities or terminal regions differ, such that release from the soma takes longer (with latencies as long as seconds, compared with synaptic transmission in milliseconds) and requires a higher frequency of action potentials [116] and may occur via dense core vesicles that also contain neuropeptides [117]. This slow release at the LC cell body in response to high frequency action potentials activates local Ī±2A auto-receptors, which should inhibit activity in the LC cell body and thereby decrease noradrenaline release in neocortex [118].
Cerebral amyloid angiopathy-related cardiac injury: Focus on cardiac cell death
2023, Frontiers in Cell and Developmental BiologySleep-Wake Disorders in Alzheimer's Disease: A Review
2022, ACS Chemical NeuroscienceLocus coeruleus in memory formation and Alzheimer's disease
2021, European Journal of Neuroscience