Insights Into The Pathogenesis Of Neurodegenerative Diseases: Focus On Mitochondrial Dysfunction And Oxidative Stress Part 4

Another commonly described aspect of PD is impaired mitochondrial dynamics and altered mitochondrial morphology, with either elongated or fragmented mitochondria [334,335]. 

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Impaired mitochondrial fusion, possibly related to the diminished levels of the short form of Opa1 described in brain samples of patients with idiopathic PD [336], contributes to the degeneration of nigral dopaminergic neurons, as does the interaction of mutant LRRK2 with Drp1, which promotes mitochondrial fission [337]. 

α-synuclein can also bind to the OMM and decrease the mitochondrial fusion rate [338], which, together with increasing the Mfn1 and Mfn2 levels, promotes fragmentation and shortening of mitochondria [339]. 

In addition, mutant LRRK2 affects mitochondrial trafficking by interfering with MIRO1 removal, resulting in the accumulation of MIRO1, which binds dynein and kinesin (microtubule motors) to mitochondria [340]. 

An interesting finding is a need to acidify the synaptic vesicles for proper loading of dopamine into these vesicles [341], a task performed by vacuolar ATPases that requires proper levels of ATP [330]. 

As such, in energy-deficient conditions, dopamine is improperly packed into synaptic vesicles and its cytoplasmic levels increase, creating conditions for its auto-oxidation [342].

6.3. Oxidative Stress in Amyotrophic Lateral Sclerosis

ALS is the third most common neurodegenerative disease, after AD and PD [16], occurring both sporadically (90–95% of cases) and as an inherited disease caused by genetic mutations. 

Many mutations leading to familial ALS cases have been described, the most common ones being mutations in SOD1, FUS (fused in sarcoma/translocated in liposarcoma or heterogenous nuclear ribonucleoprotein P2), C9orf72 (chromosome 9 open reading frame 72), and TARDP (transactive response DNA binding protein 43) [343,344], the study of which can help identify the pathophysiologic mechanisms of the disease. 

Decreased glucose metabolism with reduced ATP generation was reported in the cerebral cortex of SOD1G93A mice before the clinical picture of ALS emerged, while the spinal cord exhibited these abnormalities only in later stages [345]. 

Similar abnormalities were observed in human patients as well [346], possibly related to the downregulation of two key enzymes in glycolysis, PGK (phosphoglycerate kinase) and PGM2L1 (phosphoglucomutase-2-like 1) [347]. 

It appears that this metabolic disturbance does not affect neighboring astrocytes [348]. In response, neurons upregulate glycolysis [349] at the expense of increasing oxidative stress or may turn toward alternative sources of energy such as ketone bodies [350]. 

Beta-hydroxybutyrate facilitates oxidation of NADH and increases the NAD+/NADH ratio, thereby inhibiting mitochondrial ROS production [351] and activating SIRT1 and SIRT3 [31]. 

SIRT1, through deacetylation, alters the activity of the PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-α)/ERR-α (estrogen-related receptor α) complex, with important roles in mitochondrial biogenesis regulation [350,352]. Disturbed cellular calcium handling is another feature described in motor neurons of patients with ALS as well as in vitro and in vivo models expressing mutant SOD1 [353]. 

After AMPA activation, the recovery of physiological calcium concentrations is delayed in motor neurons of ALS models [354], rendering them susceptible to Ca2+-induced excitotoxicity [355]. In addition, analysis of motor neurons from patients with TDP-43 mutations showed an upregulation of AMPA and NMDA receptors and an imbalance between MICU1 and MICU2 leading to reduced mitochondrial calcium uptake [356]. 

Mitochondrial quality control was also found deficient, with abnormally swollen and vacuolated organelles distributed mainly in the cell body and proximal axon of motor neurons [357]. Normally, mitochondrial mitophagic receptors OPTN and NDP52 target mitochondria through their ubiquitin-binding domain and recruit autophagosomes [358]. 

Mutations of OPTN and TBK1, encoding an OPTN-containing kinase, were found in patients with ALS [359], leading to impairments of mitophagy and accumulation of damaged mitochondria which further decrease glucose metabolism and ATP generation. 

Excessive ROS activates Drp1, with consequent increased mitochondrial fission, while reduced ATP levels cause impaired autophagy and decrease proteasomal protein degradation with subsequent accumulation of protein aggregates which can trigger ER stress [360]. 

Although oxidative stress may not be the triggering factor, it likely exacerbates ALS progression, and, again, mitochondria significantly contribute to the generation of ROS. 

The SOD1 mutation diminishes the affinity of Cu/ZnSOD for Zn, altering its antioxidant properties [361], and to a higher load of DNA damage, possibly due to a loss of nuclear protection [350]. The oxidants/antioxidants ratio is supplementally altered by the reduced levels of GSH found in the motor cortex of ALS patients in comparison with healthy volunteers [362]. 

The altered calcium homeostasis leads to mitochondrial dysfunction and the activation of intrinsic (through the mitochondrial release of death signals) or extrinsic (through specific ligands binding to death receptors like Fas or DR6-death receptor 6) pathways of apoptosis [363]. 

Motor neurons in affected regions of ALS patients show increased levels of p53 [364], possibly caused by reduced proteasomal degradation of p53 [365], which leads to a decrease in Bcl-2 and an increase in Bax, Fas, and caspases 8 and 3 [366]. 

In addition, astrocytes and microglia are activated, leading to chronic inflammation and supplemental generation of ROS. Cultures of rat astroglia exposed to CSF from ALS patients showed increased release of inflammatory cytokines IL-6 and TNFα, reduced antiinflammatory cytokine IL10, increased generation of cyclooxygenase-2 and prostaglandin E2, and downregulation of trophic factors such as GDNF (glial cell-derived neurotrophic factor) or VEGF (vascular endothelial growth factor) [367]. 

Moreover, astrocytes from ALS patients release neurotoxic factors able to damage motor neurons through a Bax-dependent mechanism [368] and proliferate to surround degenerating motor neurons and produce molecules that inhibit axonal regrowth [369]. 

Activated microglia are also toxic to motor neurons. In studying the effects of TDP43 mutation, microglial activation led to an NF-κB and NLRP3 (NLR family pyrin domain containing 3) inflammasome-dependent cascade which damaged motor neurons, while in the absence of microglia, motor neurons were able to survive [370]. 

Further, blocking the NF-κB signaling pathway in microglia rescued motor neurons in an animal model of ALS [362]. Table 2 summarizes the abnormal proteins associated with the three neurodegenerative diseases discussed and their deleterious actions on mitochondrial function.

7. Translating Theoretical Knowledge into Therapy

7.1. Targeting Oxidative Stress and Mitochondrial Dysfunction in Alzheimer's Disease

Clinical trials on disease-modifying therapies have mostly failed, AD treatment proving one of the most challenging areas in modern medicine despite the increasing incidence and prevalence of the disease [387]. 

Currently, there are six FDA-approved drugs used for the treatment of AD, four of which (tacrine, donepezil, rivastigmine, and galantamine) are acetylcholinesterase inhibitors, memantine is an NMDA antagonist, while the very controversially recently approved aducanumab is an amyloid beta-directed monoclonal antibody [388]. 

Except for the last molecule, none of them are disease-modifying. In a long list of trials marked by inconclusive results or failures, several antioxidant molecules have been repeatedly evaluated. 

Curcumin can scavenge free radicals (ROS or reactive nitrogen species) [389], inhibit the activity of enzymes involved in free radical generation such as cyclooxygenases and xanthine oxidase [390], modulate the activity of endogenous antioxidants such as glutathione peroxidase, catalase, and superoxide dismutases [391], to diminish lipid peroxidation, and to reduce the expression of NF-κB, ERK, inducible nitric oxide synthase, and inflammatory cytokines IL-1β and IL-6 [392]. 

The efficacy of 24-week curcumin supplementation on AD progression has been evaluated with inconclusive results in a phase 2 randomized, double-blind, placebo-controlled trial (NCT 00099710) [393], followed by a second pilot study of curcumin and Gingko extracts administered over 6 months (NCT00164749), the results of which were not released to date [394]. 

Another active trial, NCT01811381, aims to evaluate the efficacy of curcumin in association with yoga in patients with mild cognitive impairment [394]. Resveratrol has been shown to enhance the PI3K/Akt pathway and the nuclear translocation of Nrf2 [395], to suppress NF-κB and MAPK pathway activation, and to attenuate the microglial release of TNF-α and pro-inflammatory IL-1β [396]. 

A phase 2, double-blind, placebo-controlled study (NCT01504854) of the effect of resveratrol supplements in patients with probable AD has not yet published the results [394]. NCT00678431 is another completed study evaluating whether dietary supplementation with Resveratrol, glucose, and malate can slow the progression of AD. 

According to the published results, the differences between the active and placebo arms were not statistically significant [397]. A currently recruiting phase 1 study (NCT02502253) will assess BBB penetration and bioavailability of a grape seed extract as well as its efficacy in mild cognitive impairment, prediabetes, and type 2 diabetes mellitus [394]. 

As an antioxidant, quercetin scavenges free radicals [398], upregulates antioxidant enzymes such as glutathione transferase, glutathione peroxidase, SOD, catalase, and thioredoxin [398], and induces the Nrf2-ARE pathway [399]. 

The SToMP-AD trial (Senolytic Therapy to Modulate Progression of Alzheimer's Disease, NCT04063124) is an ongoing phase I/II trial assessing bioavailability and safety of dasatinib + quercetin in old adults with early-stage AD, while ALSENLITE, NCT04785300 is currently recruiting by invitation participants in phase I/II trial to assess safety and tolerance of the combination [394]. 

Sulforaphane was able in animal models of AD to modulate the Nrf2/ARE pathway, inhibit NFκB, and upregulate neurotrophin expression [400]. An ongoing randomized, double-blind, placebo-controlled trial (NCT04213391) aims to assess the safety and efficacy of sulforaphane in mild to moderate Alzheimer's disease patients [394]. 

Modest cognitive beneficial effects in AD patients were obtained with another dietary antioxidant supplement, soy isoflavone, in a placebo-controlled, double-blind pilot study (NCT00205179) which randomized 73 patients [401]. 

8-hydroxy daidzein, a compound from fermented soy, exhibits antioxidant properties by quenching ROS, inhibiting microglial TNF-α, and IL-6 release, and upregulating the Nrf2 antioxidant and Akt/NF-κB antiinflammatory pathways [402]. 

Chlorogenic acid, the main compound of coffee, was able in vitro to reduce intracellular ROS accumulation, stop the activation of α-secretases, BACE-1, or MAPK, and attenuate GSH depletion [403]. In animal models of AD, polyphenols from coffee reduced hippocampal amyloid plaque burden, thereby attenuating memory impairments and cognitive dysfunction [404]. 

CAFCA (NCT04570085) is a multicenter, randomized, double-blind, placebo-controlled trial planned by the University of Lille, aiming at evaluating the effect of a 30-week caffeine treatment on cognitive function in early and moderate stages of Alzheimer's disease [394]. 

Lipoic acid is a molecule with anti-inflammatory functions, able to reduce NF-κB activity in vitro in cells stimulated with TNF-α [405], and able to recycle vitamins C, E, and glutathione [406]. 

A small phase I/II trial randomized 39 AD patients to receive lipoic acid, fish oil, or placebo and evaluated the rate of cognitive impairment over 12 months, showing promising results [407] and has been followed by another phase I/II study, NCT01058941, with 67 participants followed over 18 months, the results of which have not yet been published. 

Other trials with antioxidants have also been performed or are underway. For example, NCT00117403 was a phase 1 trial with the active arm taking a combination of vitamins E, and C, lipoic acid, and coenzyme Q10 for 4 months. Although CSF analysis indicated a reduction of markers of oxidative stress, the investigators cautioned against a more rapid cognitive decline [408]. 

A prospective cohort study with 4246 participants (PREADVISE, NCT00040378) followed for 7–12 years concluded that neither vitamin E nor selenium could influence the rate of cognitive decline [409]. 

Moreover, a phase 3 trial comparing the added effect of tocopherol (TEAM-AD, NCT00235716) revealed that vitamin E showed a modest benefit over placebo in slowing cognitive decline but did not add to the effect of memantine [410]. 

A currently recruiting phase 1 study, NCT04430517, will assess the effect of oral 1000 mg of nicotinamide riboside intake for 12 weeks on redox status, GSH levels, and mitochondrial function as well as on cognition in participants with mild cognitive impairment of AD [394], while a phase 1 trial of supplementation of glycine, alanine, and N-acetylcysteine (Glutathione in Alzheimer's disease, NCT04430517) for 24 weeks is registered but not yet recruiting [394]. 

Latrepirdine has been shown in preclinical studies to prevent lipid peroxidation and inhibit opening of the MPTP as well as voltage-gated calcium ion (Ca2+) channels in neurons, protecting against Aβ-induced neurotoxicity [411], while having very low acetylcholinesterase-inhibitory action, as opposed to other antihistamine drugs. 

In an 8-week open-label pilot study on 14 AD patients, latrepirdine showed clinical benefits [411], which prompted a phase 2 randomized, double-blind, placebo-controlled trial of 60 mg latrepirdine orally for 26 weeks in 183 AD patients (NCT00377715), which confirmed the positive effect on cognition, behavior, and global function [412]. 

However, the CONNECTION trial (NCT00675623), a phase 3 clinical trial of 60 mg latrepirdine for 6 months in 598 patients could not demonstrate any significant effect of the drug compared to placebo [413], and neither could CONCERT (NCT00829374), a phase 3 clinical trial comparing two doses of latrepirdine to placebo in 1003 patients. 

A meta-analysis of several studies with latrepirdine in mild-to-moderate AD patients concluded that despite some modest beneficial effects on behavior, cognition, and functional status are not influenced [414].

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