Revisiting the Clinical Link Between Alzheimer's Disease and Depression Through the Ca2+/Camp Signalling Interaction

Abstract

The scientific literature has recently debated (more intensively) the clinical link between Alzheimer ́s disease (AD) and Depression [1]. 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 [Ca]c [2]. 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 [3]. Thus, if Ca2+ signalling dysregulation may be such an upstream issue for AD, then sustained elevations of neuronal [Ca]c may be a reasonable clinical link between AD and Depression, because the sustained elevations of [Ca]c may also lead to neuronal cell death in these structures (limbic brain structures and hippocampus), which are related to the development of Depression.