Mitochondria- and Oxidative Stress-Targeting Substances in Cognitive Decline-Related Disorders: From Molecular Mechanisms to Clinical Evidence

Abstract

Alzheimer's disease (AD) is the most common form of dementia affecting people mainly in their sixth decade of life and at a higher age. It is an extensively studied neurodegenerative disorder yet incurable to date. While its main postmortem brain hallmarks are the presence of amyloid-β plaques and hyperphosphorylated tau tangles, the onset of the disease seems to be largely correlated to mitochondrial dysfunction, an early event in the disease pathogenesis. AD is characterized by flawed energy metabolism in the brain and excessive oxidative stress, processes that involve less adenosine triphosphate (ATP) and more reactive oxygen species (ROS) production respectively. Mitochondria are at the center of both these processes as they are responsible for energy and ROS generation through mainly oxidative phosphorylation. Standardized Ginkgo biloba extract (GBE), resveratrol, and phytoestrogens as well as the neurosteroid allopregnanolone have shown not only some mitochondria-modulating properties but also significant antioxidant potential in in vitro and in vivo studies. According to our review of the literature, GBE, resveratrol, allopregnanolone, and phytoestrogens showed promising effects on mitochondria in a descending evidence order and, notably, this order pattern is in line with the existing clinical evidence level for each entity. In this review, the effects of these four entities are discussed with special focus on their mitochondria-modulating effects and their mitochondria-improving and antioxidant properties across the spectrum of cognitive decline-related disorders. Evidence from preclinical and clinical studies on their mechanisms of action are summarized and highlighted.

Figure 1

Common mitochondria-related targets of natural substances in neuroprotection. In AD, the precursor of amyloid protein APP is cleaved sequentially by β- and γ-secretases leading to the production of Aβ peptides, their aggregation, and the formation of extracellular plaques. Different Aβ species exist, but Aβ_1-42 is one of the most abundant and is the one that is mainly deposited in the brain due to its hydrophobic and fibrillogenic nature. AD is associated with electron transport chain (ETC) impairments leading to decreased ATP levels and basal respiration, with a decrease of antioxidant defenses and an increase of ROS production by complex I and complex III (orange dashed arrows). Globally, Gingko biloba, resveratrol, and phytoestrogens have been shown to protect against cell death in AD through a common mechanism of action by reducing abnormal aggregation of Aβ, amyloid beta (Aβ) toxicity, oxidative stress, mitochondrial impairments leading to neuronal dysfunction, and apoptosis. Gingko biloba, resveratrol, and phytoestrogens are suggested to exert a beneficial effect in AD affected neurons, but their specific mechanisms of mitochondrial interaction are not fully described yet. ↓: AD-related decrease. The green circle indicates the common mitochondria-related targets of GBE, resveratrol, phytoestrogen, and allopregnanolone.

Figure 2

The effects of Aβ, hyperphosphorylated tau, and standardized Ginkgo biloba extract (GBE) on mitochondrial function in AD. It has been shown that mitochondrial dysfunction is a key feature in AD and plays a pivotal role on the onset of the disease. While defining the chronologically first hallmark of the disease can be puzzling, there is evidence about mitochondrial dysfunction being the first hallmark at the early stages of AD with Aβ occurring as a result. Aβ has been shown to cause a decline in OXPHOS, taking place at the ETC, which leads to defective complexes IV and V and decreased ATP production. Faulty OXPHOS function results in the production of ROS which, when in excess, cannot be counterbalanced by the antioxidant enzymes like GSH-Px and SOD. ROS can cause membrane lipid peroxidation and instable MMP. Hyperphosphorylated tau inhibits complex I activity. However, GBE has been proven to reduce Aβ aggregation and tau hyperphosphorylation and to enhance OXPHOS, activities of complexes, and ATP levels, as well as to restore MMP. ROS and consequently lipid peroxidation are reduced due to GBE, while the extract has the ability to enhance SOD and GSH-Px activity and also induce mitochondrial biogenesis. ↓: represents increase; ⟂: represents inhibition.

Figure 3

Neuroprotective effects of resveratrol in AD. The precursor of amyloid protein APP is cleaved sequentially by β- and γ-secretases leading to the production of Aβ and their aggregation. Resveratrol increases the clearance of Aβ peptides through the activation of AMPK. Resveratrol plays an important role in the neuroprotective properties as it reduces Aβ neurotoxicity by phosphorylating PKC-δ. Damaged mitochondria generate ROS which are implicated in apoptosis. iNOS and COX-2 also enhance the production of ROS. Resveratrol exerts antioxidant properties and attenuates oxidative damage by decreasing iNOS and COX-2 levels. Resveratrol also protects mitochondria by increasing the expression of ROS-inactivating enzymes GPx1 as well as SOD1 and by reducing the expression of the ROS-producing enzyme Nox4. Resveratrol also influences the Aβ-induced apoptotic signalling pathway by inhibiting the expression of caspace-3, Bax, FOXO, and p53 by blocking the activation of JNK and by restoring the decrease of Bcl-2 expression, as well as by inhibiting the increase of NF-κB DNA binding. Mitochondrial biogenesis is induced by resveratrol through SIRT1 activation and deacetylation of PGC-1α. Resveratrol was also able to protect hippocampal neurons by alleviating cognitive impairment and reducing neuronal loss via modulating the janus kinases, extracellular signal-regulated kinases, and signal transducers, as well as the signalling pathway of the activators of transcription (JAK/ERK/STAT).

Figure 4

Standardized Ginkgo biloba extract (GBE) LI 1370 (Vifor SA, Switzerland) (100 μg/ml) increased neurite outgrowth of SH-SY5Y neuroblastoma cells after 3 days of treatment in 3D cell culture. Pictures were taken using a cell imaging multimode reader Cytation3 (Biotek Instruments Inc., X20 in black and white) after immunostaining (IMS, βIII-tubuline/Alexa488). Compared to the untreated SH-SY5Y cells (CTRL, (a)), 100 μg/ml of GBE (b) was efficient in increasing the formation of neurites.

Figure 5

Neuroprotective effects of allopregnanolone (AP) in AD. AP has been proven to reduce Aβ aggregation-induced cell death. It exerts a neuroprotective effect against oxidative stress-induced cell death via the improvement of the cellular and mitochondrial energy by enhancing the OXPHOS and ATP levels. AP ameliorates the mitochondrial redox environment by decreasing ROS and by improving the activity of the enzyme MnSOD. AP also has beneficial effects on bioenergetic enzymes such as PDH and αKGDH implicated in the TCA cycle. AP ameliorates cholesterol homeostasis and clearance for the biosynthesis of neurosteroids by raising the expression of PXR and LXR. AP promotes repair and renewal of neurons leading to restored cognitive performances in AD.

Figure 6

Modulation of mitochondrial function by estrogen and phytoestrogen. Less evidence is provided for the direct effects of phytoestrogen on mitochondria compared to estrogen, but antioxidant properties were demonstrated.