Parallels between major depressive disorder and Alzheimer's disease: role of oxidative stress and genetic vulnerability

Abstract

The thesis of this review is that oxidative stress is the central factor in major depressive disorder (MDD) and Alzheimer's disease (AD). The major elements involved are inflammatory cytokines, the hypothalamic-pituitary axis, the hypothalamic-pituitary gonadal, and arginine vasopressin systems, which induce glucocorticoid and "oxidopamatergic" cascades when triggered by psychosocial stress, severe life-threatening events, and mental-affective and somatic diseases. In individuals with a genomic vulnerability to depression, these cascades may result in chronic depression-anxiety-stress spectra, resulting in MDD and other known depressive syndromes. In contrast, in subjects with genomic vulnerability to AD, oxidative stress-induced brain damage triggers specific antioxidant defenses, i.e., increased levels of amyloid-β (Aβ) and aggregation of hyper-phosphorylated tau, resulting in paired helical filaments and impaired functions related to the ApoEε4 isoform, leading to complex pathological cascades culminating in AD. Surprisingly, all the AD-associated molecular pathways mentioned in this review have been shown to be similar or analogous to those found in depression, including structural damage, i.e., hippocampal and frontal cortex atrophy. Other interacting molecular signals, i.e., GSK-3β, convergent survival factors (brain-derived neurotrophic factor and heat shock proteins), and transition redox metals are also mentioned to emphasize the vast array of intermediates that could interact via comparable mechanisms in both MDD and AD.

Fig. 1

Example of ad–mdd interaction pathogenetic model. Proposed molecular interaction between two neuropathologies such as MDD and AD. It is impossible to avoid complexity, by reason of the many genotypes and phenotypes involved. Two molecular “cascades” are sketched and greatly simplified, as many more enzymes, proteins, transcription factors, and genome changes, to name a few, are involved, opening new fields of research and therapeutic applications. a Cortisol depression cascade. The currently established genome of more than 40 % of chronic, long-standing, depressed–anxious–stressed patients—which are short mutant alleles of the 5-HTT carriers—induces a vulnerability to the personality threshold to withstand normal and severe life adversities and diseases. Significantly, in more (40-50 %) carriers of 5-HTT short alleles than not, they develop depressive major crises or chronic dysthymia with long-term, severe anxiety and stress. Chronic depression elevates corticotrophin release factor, activating the hypothalamus–pituitary–adrenal axis and increasing cortisol levels significantly, particularly in hippocampal areas with glycocorticoid and mineralocorticoid receptors. Neurotransmitters are led to dyshomeostasis and glucose uptake falls in hippocampal neurons. Glutamate receptors (NMDARs) in particular are robustly activated, and intracellular Calcium elevated. These two factors contribute to oxidative stress and, directly, to the inhibition of hippocampal neurogenesis and atrophy, impairing its inhibition of CRF and elevating its levels, closing the cycle. b The “Aging Alzheimer Cascade” progresses during late life, influencing and influenced by free radicals—ROS and RNS, oxidative stress, redox transition metals—iron (Fe) and copper (Cu), and increased deposition of amyloid-β peptide (Aβ) as a consequence of increased levels of amyloid-β protein precursor (AβPP); and of Tau and Apolipoprotein Eε4 (ApoEε4). During aging, two main factors may contribute to close the cycle: 1—accumulation of free radicals-oxidative stress with damage to proteins, fatty acids, glycoproteins, and DNA; and 2—genetic vulnerability: mutant alleles in specific genes leading to dysfunction of the many complex—defense and pathological—roles of the key proteins in AD: AβPP, Aβ, Tau, and ApoE4; possible accumulation, with long-term life repetitions, of “transcriptional continuity errors,” and other unknown factors. Finally, the advent of AD closes the cycle, since it means fast brain aging. The figure does not indicate whether AD is the normal final pathway—a closed system with no entries or deaths, at 100 years of age, persons without AD are the absolute minority (17–20 %); and AD individuals are the majority (70–80 %) (Rodrigues et al. 2010). This Figure, which exhibits the various interactions of both cascades, raises the question of whether these pathologies are analogous or very close biological processes which occur sequentially during the life cycles

Fig. 2

Interaction of transition metals—amyloid beta peptide—apolipoprotein Eε4—MDD—AD. An example of how chronic depression might interact with metal redox systems and antioxidant defenses of the Fenton reaction and Haber–Weiss metal cycle, which can lead to MCI and AD, if oxidative stress and genetic vulnerability to neurodegeneration cannot be efficiently controlled. A. Chronic depression is associated with cortisol increased levels which, through the “cortisol cascade” (see Fig. 1) in hippocampus, leads to dyshomeostasis of the neurotransmitter systems, particularly glutamate elevation and consequent Calcium intracellular increased concentration. The key interaction process between AD and MDD is oxidative stress originated from neurotoxicity, once Calcium-elevated levels generate ROS and RNS; and free radicals. By its turn, depression-generated OS interacts with aging and AD, phenotypes known to be OS induced (not shown in the sketch). By four ways, this interaction might occur: inducing Aβ elevation as antioxidant defense; increasing strong free radicals such as OH· and others; contributing to Aβ oligomer formation; and through hippocampal atrophy in brain regions where AD shows atrophy. In the figure, some factors that may be intermediary between both illnesses are shown as examples (many other molecular processes exist that are not shown here): GSK-3β increases its intracellular level and activates TAU hyperphosphorylation contributing to NFTs formation. Brain-derived neurotrophic factor (BDNF) levels decline as a result of the “cortisol cascade”; BDNF levels also decline in AD. In both cases, survival functions and nuclear synthesis counter neural apoptosis and other neurodegenerative processes are impaired with drop in BDNF. b We illustrate how oxidative phosphorylation creates free radicals (OH· hydroxyl radical for example) and how antioxidants usually control homeostasis (SOD1, superoxide dismutase; GPx1, GSH-Px) avoiding oxidative stress (transforming free radicals in water, H₂O, or lipid alcohols, LOH). However, with genetic vulnerability—as in cases of mutant alleles of the proteins APP (amyloid precursor protein), PS1, PS2 (pre-senilins 1 and 2), τ (tau), and ApoEs (apolipoproteins E) whose functions are currently thought to normally protect against oxidative stress and neurodegenerative processes—redox transition metals such as Fe and Cu may not be efficiently controlled because the binding on macromolecular complexes—ApoEε4, Aβ, and Fe—is in higher neural levels than normally. These complexes might be excessively created and lead to insoluble Aβ oligomers (instead of soluble Aβ monomers) which turn on amyloid deposits. Genetic vulnerability in chronic depression that reinforces MCI, AD, or other neurodegenerative illnesses has been shown in Fig. 1

Fig. 3

Interaction among amyloid beta peptide, apolipoprotein e, and transition redox metals –macromolecular model. Illustration of how macromolecular complexes ApoEε4-Aβ oligomers-redox transition metals might be maintained in bound state; and the molecular dynamics which may sustain them in Aβ monomer solution or, in case of excessive β-Amyloid peptide formation and ApoEε4 disproportionate interference, in Aβ insoluble oligomers. a A model of the macromolecular complex dynamics is presented. Fe+++ is bound to Aβ as it takes an electron from it, turning on Aβ+ . By the Fenton reaction, Fe++ then generates the strong hydroxyl radical. This and other free radicals are buffered by antioxidants GPx1, catalase, Ascorbate, Vit E, and others. Using antioxidants, Fe++, through the Haber–Weiss cycle, regenerates Fe+++, and maintaining its binding to Aβ+ . In its turn, ApoEε4 may be bound to Aβ+ through histidine NH bonds. Van der Waal intermolecular dispersion forces impair aggregation of Aβ peptide and it stays free as soluble monomers. b If there is impairment of MMC dynamic homeostasis, particularly when Aβ peptide increases excessively by oxidative stress, genetic vulnerability, or there is overload of ApoEε4 or redox transition metals (RTMs) bias impairing Fe dynamic function, then histidine NH bonds get stronger bonds which cannot be separated by Van der Waal forces. The result may be the aggregation and deposition of the insoluble oligomers formed

Fig. 4

18 FDG (fluorodeoxyglucose) uptake in the cortical and subcortical regions at the level of the basal ganglia in late-life depression, DAT, and an age-matched control. Orange and red show areas of high FDG uptake; green and blue represent regions with low FDG uptake. The right side of the image represents the left side of the brain and vice versa. Note the widespread decline in FDG uptake that occurs in late-life depression and DAT relative to the control