Revisiting the Clinical Link Between Alzheimer's Disease and Depression Through the Ca2+/Camp Signalling Interaction
Received Date: Apr 23, 2018 / Accepted Date: Apr 26, 2018 / Published Date: Apr 30, 2018
Keywords: Alzheimer´s disease; Depression; Ca2+/cAMP signaling interaction
The scientific literature has recently debated (more intensively) the clinical link between Alzheimer´s disease (AD) and Depression . Despite the accumulation of the amyloid-β (Aβ) in the brain (amyloid cascade hypothesis) has been considered the main issue in the arena of AD, this hypothesis does not explain the fact that there must be changes that may occur during aging process that result in increased production and aggregation of Aβ, thus culminating in the status of AD. Evidences suggest that Ca2+ signalling dysregulation may be such an upstream issue. Environmental issues that prevent amyloid genesis (caloric restriction, cognitive stimulus and antioxidants) virtually restore the neuronal Ca2+ homeostasis, whereas factors that enhance amyloid genesis dysregulate Ca2+ homeostasis. These evidences are supported by experiments which demonstrated that exposure of cultured neurons to Ca2+ ionophores enhances the production of Aβ, as do conditions such as ischemia that cause sustained elevations of Ca2+ concentrations [Ca2+]c .
In addition, considering that the neuron uses Ca2+ signals to regulate the release of neurotransmitter, and that the deficit of neurotransmitter release is causally related to the clinical signs of Depression, then Ca2+ signalling is also one of the main actors in the arena of Depression. Indeed, the monoamine hypothesis of Depression continues to be one actor that dominates the field, which hypothesizes that an imbalance in monoaminergic neurotransmission culminates in the deficit of neurotransmitter release. Despite this hypothesis, pre-clinical and clinical studies have also shown that Depression can lead to cell loss in limbic brain structures, which are critically involved in the status of depression, including the hippocampus . Thus, if Ca2+ signalling dysregulation may be such an upstream issue for AD, then sustained elevations of neuronal [Ca2+]c may be a reasonable clinical link between AD and Depression, because the sustained elevations of [Ca2+]c may also lead to neuronal cell death in these structures (limbic brain structures and hippocampus), which are related to the development of Depression.
Furthermore, our discovery entitled “calcium paradox” due to interaction between Ca2+ and cAMP signalling pathways (named by us as Ca2+/cAMP signalling interaction) has supported the better understanding of the pathophysiology of the neurological and psychiatric diseases [4-7]. Our proposal involves pharmaceuticals already approved, and clinically safe, from non-neurodegenerative therapy indications (hypertension). Thus, combined with improvements in the lifestyle issues (caloric restriction, cognitive stimulus and antioxidants), it may allow sustained increments in the life quality of age-related neurological patients, opening a large path for the improvement of new pharmacological strategies (more effective) for the treatment of these diseases. Then, if sustained elevations of neuronal [Ca2+]c may be a reasonable clinical link between AD and Depression, then the Ca2+/cAMP signalling interaction may also be disrupted in AD and Depression. We nowadays know that neuronal Ca2+ signalling involves an intricate interaction between Ca2+ influx across plasma membrane through voltage-activated Ca2+ channels (VACC), TRP (transient receptor potential) channels, and Ca2+ release from intracellular Ca2+ stores via IP3R, and RyR channels in the endoplasmic reticulum (ER) [4-7]. Intracellular Ca2+ release via IP3R is triggered by the second messenger IP3, which is produced following activation of metabotropic receptors coupled to phospholipase C. In addition, neuronal RyR functions as Ca2+-activated Ca2+ channels which further amplifies Ca2+ signals, originating from other sources. Mitochondria also plays a significant role in shaping neuronal Ca2+ signalling by utilizing potent mitochondrial Ca2+ uptake mechanisms. Ca2+ uptake into mitochondria plays an important role in neuronal physiology by stimulating mitochondrial metabolism and increasing mitochondrial energy production. Excessive Ca2+ uptake into mitochondria can lead to opening of a permeability transition pore (PTP) and apoptosis. Owing to its importance for neuronal function, Ca2+ signalling in neurons is tightly compartmentalized, and regulated within signalling microdomains which involve, for example, functional coupling between VACC and intracellular Ca2+ release channels, or between ER Ca2+ release and Ca2+ uptake into mitochondria. Indeed, evidences reinforce the idea that compartmentalization of adenylyl cyclases (AC) may also cause functional compartmentalization of [cAMP]c oscillations. The more exact and specific compartmentalization takes place within several AC in proximity to VACC. Thus, in excitable cells, Ca2+-regulated AC are controlled by Ca2+ entry through VACC [4-7]. Not surprisingly, the form of regulation described in most studies is that in which AC are controlled by Ca2+ influx through VACC. Then, if sustained elevations of neuronal [Ca2+]c may be a reasonable clinical link between AD and Depression, thus the cAMP signalling pathways may also be dysregulated through Ca2+/cAMP signalling interaction. Additional experiments in this field, using fluorescent probes which target Ca2+ and cAMP may add interesting results for this challenge hypothesis [8-10].
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Citation: Bergantin LB (2018) Revisiting the Clinical Link Between Alzheimer’s Disease and Depression Through the Ca2+/Camp Signalling Interaction. Brain Disord Ther 7: e127. DOI: 10.4172/2168-975X.1000e127
Copyright: © 2018 Bergantin LB. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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