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Parkinson disease (PD) is a prevalent neurodegenerative disorder affecting dopaminergic neurons in the substantia nigra (SN). Neuroinflammation has a vital role in PD pathophysiology.

This study assesses whether the neuroinflammatory molecular and signaling pathways could be associated with PD’s progression and clinical manifestations.

PubMed, Web of Science, Embase, and Scopus databases were investigated from 2006 until December 2023 to find relevant studies. All observational studies written in English and reporting qualitative or quantitative information on the relationship between neuroinflammation and PD were included in this review.

Finally, 41 papers were involved in the systematic review. According to the involved studies, it is suggested that tumor necrosis factor-α, C-reactive protein, microsomal prostaglandin E synthase1, toll-like receptor-4 (TLR-4), CCL23, CCL25, TNF-receptor superfamily member 9, EV-derived cytokines, transforming growth factor alpha, vascular endothelial growth factor A, SH-SY5Y, TLR 2/4, miR-485-3p, leucine-rich repeat kinase 2, and α-synuclein may be upregulated in the PD patients. Also, the activity of astrocytes and microglial cells was reported to be increased in PD patients through different mechanisms. 

This study demonstrated that the neurodegeneration in PD could be initiated by α-synuclein protein aggregation and the activation of astrocytes and microglial cells, which leads to neuroinflammation characterized by inflammatory responses in neurons. Finally, chronic neuroinflammation could be the cause of dopaminergic neuronal death in SN. The impact of both single and all factors involved in neuroinflammation was assessed to plan further studies in a particular pathway to intercept the onset of inflammatory pathways in favor of therapeutic purposes.

In recent years, many studies have suggested the essential role of the prolyl isomerase Pin1 enzyme in protecting against age-related neurodegeneration in Alzheimer's disease (AD). This enzyme is involved in the conformational changes of the two key proteins including amyloid precursor proteins (APP) and tau protein from dysfunctional (cis) to properly functional (trans) form. Promoting non-amyloidogenic degradation of APP, restoring tau function in microtubule assembly, and inducing tau dephosphorylation are among the main results of the Pin1 physiological functions. In AD, the lack of Pin1 activity slows down the rate of isomerization, which promotes the amyloidogenic pathway and induces the formation of neurofibrillary tangles (NFTs). The exact molecular mechanisms of Pin1 dysregulation in AD have not yet been elucidated. However, the findings suggest that Pin1 may be a new target in managing AD at early stages, and investigating the regulation of its expression in neurons could help achieve this goal.

Alzheimer’s disease (AD) is a neurodegenerative brain disorder which has no effective treatment yet due to the blood barrier in the brain that limits the drugs with the potential of disease improvement. Extracellular vesicles (EVs) are biocompatible nanoparticles with a lipid membrane. These vesicles are secreted from various cells such as mesenchymal stem cells (MSCs) and can pass through biological barriers for transfer of information such as signals or be used as carriers for various proteins like Neprilysin (NEP). NEP is an active enzyme in the clearance of abnormal aggregated beta-amyloid sheets in the brain. In the present study, we used EVs to carry NEP for memory improvement in Alzheimer’s disease. For this purpose, bone marrow MSCs were isolated from rat femur. Stemness evaluation of established cells was characterized by differentiation potency and specific markers with flowcytometry. EVs were isolated from MSCs supernatant by ultracentrifugation and analyzed by scanning electron microscopy(SEM), dynamic light scattering(DLS) and western blotting. EVs were loaded with NEP by freeze-thaw cycle and then administrated intranasally in a rat model of the AD for 14 days. Our findings showed EV-loaded NEP caused a decrease in IL-1beta and also BAX but an increase in BCL2 expression level in the rat brain. Altogether, these data showed that EV-loaded NEP can improve brain-related behavioural functional which may be mediated through the regulation of inflammation and apoptosis. These findings suggest that EV-loaded NEP can be considered as a potential drug delivery system for the improvement of AD.