Oxidative Stress-mediated Lipid Peroxidation-derived Lipid Aldehydes in the Pathophysiology of Neurodegenerative Diseases

Abstract

Neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis cause damage and gradual loss of neurons affecting the central nervous system. Neurodegenerative diseases are most commonly seen in the ageing process. Ageing causes increased reactive oxygen species and decreased mitochondrial ATP generation, resulting in redox imbalance and oxidative stress. Oxidative stress-generated free radicals cause damage to membrane lipids containing polyunsaturated fatty acids, leading to the formation of toxic lipid aldehyde products such as 4- hydroxynonenal and malondialdehyde. Several studies have shown that lipid peroxidation-derived aldehyde products form adducts with cellular proteins, altering their structure and function. Thus, these lipid aldehydes could act as secondary signaling intermediates, modifying important metabolic pathways, and contributing to the pathophysiology of several human diseases, including neurodegenerative disorders. Additionally, they could serve as biomarkers for disease progression. This narrative review article discusses the biological and clinical significance of oxidative stress-mediated lipid peroxidation-derived lipid aldehydes in the pathophysiology of various neurodegenerative diseases.

Keywords: Alzheimer’s; Oxidative stress; Parkinson’s; hydroxynonenal; lipid peroxidation; malondialdehyde; neurodegenerative disorders..

Fig. (1)

Role of oxidative stress in mediation of neurodegenerative diseases. Increased oxidative stress can cause aging, and aging can also lead to oxidative stress. This leads to impaired protein folding, protein aggregation, altered metabolic pathways, mitochondrial dysfunction, and cellular calcium imbalance. These processes result in neuronal cell death and dysfunction. The initiation of neurodegeneration starts in subcortical regions and spreads across cortical regions as the disease progresses.

Fig. (2)

Lipid peroxidation process and generation of lipid aldehyde intermediates. Reactive - free aldehydes target polyunsaturated fatty acids (PUFAs) in membrane phospholipids, initiating lipid peroxidation. This process involves three steps: initiation (ROS attack PUFAs, forming lipid radicals), propagation (lipid radicals react with oxygen, forming lipid peroxyl radicals and unstable lipid peroxides), and termination (lipid radicals combine or are neutralized by antioxidants like vitamin E). Excessive lipid peroxidation disrupts cellular metabolic and signaling pathways, leading to pathological conditions, including neurological diseases.

Fig. (3)

Significance of lipid peroxidation-derived aldehydes in Parkinson’s disease. Lipid peroxidation-derived aldehydes could contribute to oxidative stress-induced pathogenesis of Parkinson’s disease (PD). α-Synuclein (αSyn), a protein involved in synaptic function, accumulates in PD, and is affected by lipid aldehydes. HNE and ONE can modify αSyn, blocking sites necessary for proteasomal degradation, which may lead to further αSyn fibril production and Lewy body formation. This impairment can disrupt dopamine production and signaling, contributing to PD.

Fig. (4)

Role of lipid peroxidation-derived aldehydes in Huntington’s disease: The mutation in the HTT gene leads to the production of toxic mutated huntingtin protein aggregates, which disrupt various cellular processes and contribute to neuronal dysfunction and death. Oxidative stress-induced lipid peroxidation-derived aldehydes play a critical role in this process by causing mitochondrial dysfunction, impairing antioxidant defenses, increasing neuronal cell death, causing DNA and protein damage, and inducing neuronal inflammation, all of which accelerate the progression of Huntington's disease.

Fig. (5)

Significance of lipid aldehydes in the pathology of Alzheimer’s disease. Increased oxidative stress during aging and elevated NOX4 levels further induce the peroxidation of membrane lipids, forming lipid aldehyde intermediates. These aldehydes could activate GSK-3B by inhibiting PP2A, leading to Tau hyperphosphorylation. They are also responsible for the accumulation of amyloid beta protein by interrupting proteasomal function, causing neuronal cell death by activating pro-apoptotic factors such as caspase 3. Additionally, they contribute to increased neuronal inflammation and astrocyte cytotoxicity, ultimately leading to Alzheimer’s disease.

Fig. (6)

Contribution of oxidative stress-induced lipid aldehydes in the pathogenesis of Amyotrophic lateral sclerosis. Oxidative stress-induced lipid aldehydes significantly contribute to the pathogenesis of Amyotrophic Lateral Sclerosis (ALS). These aldehydes are implicated in the formation of protein aggregates, DNA damage, disruption of mitochondrial functions, and alteration of cell signaling. These processes lead to increased inflammation, progressive degeneration of motor neurons, and decreased muscle contraction. These processes collectively drive the progression of ALS.