Exploring the Etiological Links behind Neurodegenerative Diseases: Inflammatory Cytokines and Bioactive Kynurenines

Abstract

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases (NDs), presenting a broad range of symptoms from motor dysfunctions to psychobehavioral manifestations. A common clinical course is the proteinopathy-induced neural dysfunction leading to anatomically corresponding neuropathies. However, current diagnostic criteria based on pathology and symptomatology are of little value for the sake of disease prevention and drug development. Overviewing the pathomechanism of NDs, this review incorporates systematic reviews on inflammatory cytokines and tryptophan metabolites kynurenines (KYNs) of human samples, to present an inferential method to explore potential links behind NDs. The results revealed increases of pro-inflammatory cytokines and neurotoxic KYNs in NDs, increases of anti-inflammatory cytokines in AD, PD, Huntington's disease (HD), Creutzfeldt-Jakob disease, and human immunodeficiency virus (HIV)-associated neurocognitive disorders, and decreases of neuromodulatory KYNs in AD, PD, and HD. The results reinforced a strong link between inflammation and neurotoxic KYNs, confirmed activation of adaptive immune response, and suggested a possible role in the decrease of neuromodulatory KYNs, all of which may contribute to the development of chronic low grade inflammation. Commonalities of multifactorial NDs were discussed to present a current limit of diagnostic criteria, a need for preclinical biomarkers, and an approach to search the initiation factors of NDs.

Keywords: Alzheimer’s disease; Parkinson’s disease; amyloid; cytokine; kynurenine; multifactorial causality; neurodegenerative diseases; neuroinflammation; prion; tau; tryptophan.

Figure A1

Flow diagram of qualitative synthesis regarding inflammatory cytokines in neurodegenerative diseases, adopted from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Figure A2

Flow diagram of qualitative synthesis regarding kynurenines in neurodegenerative diseases, adopted from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Figure 1

Initiation–progression hypothesis of neurodegenerative diseases. (a) A common pathological finding of neurodegenerative diseases (NDs) is neurodegeneration such as neural loss and gliosis. The location and distribution of neurodegeneration present corresponding neurological and psychiatric signs and symptoms. (b) Histopathological studies showed abnormal proteinaceous deposits in the degenerative neural tissues. Proteinopathies include amyloidosis, tauopathy, synucleopathy, and transactive response DNA-binding protein (TDP)-43 proteinopathy. (c) Activation of glial cells and astrocytes causes neuroinflammation, most probably the last common pathway leading to neurodegeneration. Neuroinflammation potentiates the accumulation of the abnormal proteinaceous materials in the brain tissue. (d) Neurodegeneration also causes neuroinflammation forming a cyclic potentiation. (e) The proteinopathy–neuroinflammation–neurodegeneration cycle can be triggered by multifactorial initiation factors not yet clearly defined. The genetic, environmental, infectious, nutritional, and lifestyle components are major factors which contribute to the initiation process of the NDs.

Figure 2

l-Tryptophan metabolism and the kynurenine pathway. The indole ring of l-tryptophan (TRP) is oxidized by the TRP dioxygenase (TDO) and the indolamine-2,3-dioxygenase (IDO) to produce N-formyl kynurenine (KYN). N-formyl KYN is converted by the formamidase to KYN, a substrate of three downstream metabolites: anthranilic acid (AA) by the kynureninase, 3-hydroxy-KYN (3-HK) by the KYN-3-monooxygenase (KMO), and kynurenic acid (KYNA) by KYN aminotransferases (KATs), which also convert 3-HK to xanthurenic acid (XA). XA is converted to cinnabarinic acid (CA) by autoxidation. AA and 3-HK are converted by 3-hydroxyanthranilate oxidase to 3-hydroxy-AA (3-HAA). 3-HAA is converted by 3-hydroxyanthranilate dioxygenase to 2-amino-3-carboxymuconate semialdehyde, which is further transformed into picolinic acid (PA) and quinolinic acid (QA). QA is further converted to nicotinic acid, nicotinic acid adenine dinucleotide, and nicotinamide dinucleotide (NAD⁺). Neurotoxic, oxidative KYNs are shown in orange color, neuromodulartory anti-inflammatory and antioxidant KYNs are shown in green color, and aryl hydrocarbon receptor agonists are represented by a blue dotted line.

Figure 3

The status of inflammatory cytokines and kynurenines: signs and symptoms of neurodegenerative diseases. All neurodegenerative diseases significantly increased pro-inflammatory cytokines and neurotoxic cytokines. The involvement of three representative symptoms of neurological diseases is described in lower axes of the profiles: motor dysfunction, autonomic dysfunction, and psychobehavioral symptoms.

Figure 4

Commonalities of neurodegenerative diseases. (a) In total, 30% of patients with Alzheimer’s disease (AD) develop parkinsonism, whereas over 30% of patients with Parkinson’s disease (PD) present dementia during their disease course. (b) Lewy body (LB) disorders include PD, PD with dementia, and dementia with LBs (DLB). DLB and PD with dementia share AD-type pathology and about 50% of PD with dementia is considered progression of the underling comorbidity with AD. (c) The amyloid deposits in the neurons and glial cells are characteristic to AD, and tauopathy is most prevalent in AD. The tauopathy of AD is considered secondary to the deposition of amyloid-β (Aβ). Pathognomonic to amyotrophic lateral sclerosis (ALS), TDP-43 proteinopathy is detected in up to 50% of patients with AD. The ballooned nerve cells abundant in Huntington’s disease (HD) are found in tauopathy such as in AD. Amyloid deposition is also observed in about 10% of Creutzfeldt–Jakob disease (CJD), starting with AD-like cognitive symptoms, and rapidly progressing to dementia and death. Diffuse intracellular amyloid plaques are associated with age and HIV-associated neurocognitive disorders (HAND). Increased hyperphosphorylated tau was reported in HIV-infected patients on combination antiretroviral therapies (cART). Stroke-induced secondary neurodegeneration (SND) shares many similarities to AD such as abnormal amyloid deposition.

Figure 4

Commonalities of neurodegenerative diseases. (a) In total, 30% of patients with Alzheimer’s disease (AD) develop parkinsonism, whereas over 30% of patients with Parkinson’s disease (PD) present dementia during their disease course. (b) Lewy body (LB) disorders include PD, PD with dementia, and dementia with LBs (DLB). DLB and PD with dementia share AD-type pathology and about 50% of PD with dementia is considered progression of the underling comorbidity with AD. (c) The amyloid deposits in the neurons and glial cells are characteristic to AD, and tauopathy is most prevalent in AD. The tauopathy of AD is considered secondary to the deposition of amyloid-β (Aβ). Pathognomonic to amyotrophic lateral sclerosis (ALS), TDP-43 proteinopathy is detected in up to 50% of patients with AD. The ballooned nerve cells abundant in Huntington’s disease (HD) are found in tauopathy such as in AD. Amyloid deposition is also observed in about 10% of Creutzfeldt–Jakob disease (CJD), starting with AD-like cognitive symptoms, and rapidly progressing to dementia and death. Diffuse intracellular amyloid plaques are associated with age and HIV-associated neurocognitive disorders (HAND). Increased hyperphosphorylated tau was reported in HIV-infected patients on combination antiretroviral therapies (cART). Stroke-induced secondary neurodegeneration (SND) shares many similarities to AD such as abnormal amyloid deposition.

Figure 5

Presumed progression of initiation stage and approaches for causality search of multifactorial neurodegenerative diseases. (a) The genetic, environmental, infectious, nutritional, and lifestyle components are major factors in the initiation process. The cause–effect relationships can become bidirectional. A cause becomes an effect and an effect becomes a cause, playing an initiation role in multiple reciprocal causations. Constantly changing numerous factors form an effective causative complex. The distal causative complex influences and develops the proximal causative complex in progression of the initiation phase, leading ultimately to a disease-prone state. (b) The causal assessment is performed by multi-causality and probabilistic determinism establishing classical causal criteria. Mechanistic and difference-making interpretations inform causality assessment. Incorporation of a reference case may ease reaching an interpretation of meaningful comparisons. The epistemic causality search assesses evidence which cannot be reducible by mechanistic and difference-making interpretations.