Locus Coeruleus, norepinephrine and Aβ peptides in Alzheimer's disease

Abstract

Monoaminergic brainstem systems have widespread projections that participate in many central processes and, when dysregulated, contribute to a plethora of neuropsychiatric and neurodegenerative disorders. Synapses are the foundation of these neuronal circuits, and their local dysfunction results in global aberrations leading to pathophysiological disease states. This review focuses on the locus coeruleus (LC) norepinephrine (NE) brainstem system and its underappreciated role in Alzheimer's disease (AD). Amyloid beta (Aβ), a peptide that accumulates aberrantly in AD has recently been implicated as a modulator of neuronal excitability at the synapse. Evidence is presented showing that disruption of the LC-NE system at a synaptic and circuit level during early stages of AD, due to conditions such as chronic stress, can potentially lead to amyloid accumulation and contribute to the progression of this neurodegenerative disorder. Additional factors that impact neurodegeneration include neuroinflammation, and network de-synchronization. Consequently, targeting the LC-NE system may have significant therapeutic potential for AD, as it may facilitate modulation of Aβ production, curtail neuroinflammation, and prevent sleep and behavioral disturbances that often lead to negative patient outcomes.

Keywords: adrenergic receptors; amyloid; dense core vesicles; dopamine-β-hydroxylase; inflammation; stress.

Fig. 1

Trafficking Route of APP, α-secretase, BACE1 and γ-secretase. Full length APP is synthesized in the endoplasmic reticulum and subsequently transported through the Golgi, and trans-Golgi network (TGN) where APP undergoes post-translational modifications such as glycosylation and phosphorylation during maturation. Full length APP can be transported to the cell surface in TGN-derived secretory vesicles, where APP may be cleaved by α-secretase present within the plasma membrane to produce sAPPα, or re-internalized via clathrin mediated endocytosis. Typically elevated retention within the endosome leads to increased production of the toxic amyloid beta by the β-secretase, BACE1, which is localized to and optimally cleaves in the acidic conditions of the endosome. BACE1 cleaves APP into the sAPPβ and C99 fragments, and the C99 fragment is then cleaved again by the gamma secretase also present in the endosome, to produce the amyloid beta peptide that is known to aggregate and become neurotoxic. Subsequently, Aβ may be degraded in the lysosome, or participate in the secretory pathway, where Aβ will be released into the extracellular space. Another potential site of Aβ production, still under investigation, are the large dense core vesicles (LDCVs). APP, β- and γ-secretases have been localized to LDCVs. Initial formation of LDCVs occurs at the TGN; following neuropeptide synthesis in the cell body, condensation of LDCV contents and maturation is facilitated by chromogranin peptides that reside within the LDCVs. LDCVs may be released at the soma, or undergo anterograde transport to terminal regions where they may be released away from active zones (Wang and ebrary Inc, 2008).

Fig. 2

Adrenergic Receptor Influence on Aβ production. The β2 adrenergic receptor is a Gs coupled receptor that may influence Aβ production in two ways. First, APP may be internalized with β2 following periods of prolonged stimulation, therefore allowing APP to act as a substrate for β- and γ-secretases in the endosome. Second, β2 may interact with the β-arrestin 2 protein that directly interacts with the α-1A subunit of γ-secretase, increasing its catalytic activity. The α-2A receptor is a Gi coupled receptor that influences Aβ production by disrupting the interaction of APP with SorLA, a retromer that protects APP from proteolytic cleavage.

Fig. 3

Model of proposed contribution of LC-NE Dysregulation in Alzheimer's disease. Our current working model proposes that aberrant activation of the LC at the synaptic level (a), leads to global aberrant LC activity in its widespread projection areas (A). With increased synaptic activity, increased transmission of NE may occur concomitantly with increased Aβ production in synaptic vesicles such as the LDCVs (B). Increased Aβ production and secretion may result from the described mechanisms of adrenergic receptor influence on APP processing (b). Further, the ability of NE to undergo volume transmission, engaging extrasynaptic mechanisms of transmission on neighboring neuronal and glial cells, has significant implications for the microenvironment (B, C). Finally, following a prolonged period of Aβ accumulation, cortical thinning, decreased noradrenergic transmission, and downstream loss of inflammatory modulation results in the detrimental activation of glial cells, and decreased dendritic spine density, and potentially network de-synchronization.