Neurodegeneration is a term that can be applied to several conditions which share, as common features, the progressive loss of structure and function of central nervous system (Wareham et al., 2022). Neurodegenerative diseases include a variety of pathological disease entities and clinical presentations, among these, the most prevalent are Alzheimer’s disease (AD, progressive dementia), Parkinson disease (PD, progressive movement disorder with or without dementia; Poewe et al., 2017; Leng and Edison, 2021). Although AD and PD are two distinct diseases they often appear together and share several risk factors contributing to the development and progression of the two pathologies, including aging, genetic and epigenetic factors, environmental factors (Poirier et al., 1993; Hou et al., 2019; Businaro et al., 2021; Marques-Aleixo et al., 2021). AD and PD are neurodegenerative diseases which affect memory, movement and communication. PD typically presents clinically with a tremor at rest, Bradykinesia, rigidity and gait impairments with pathological features of dopaminergic neuron loss and presence of Lewy bodies, whereas AD typically presents clinically as learning and memory loss, reductions in executive function and speech and, pathologically, is associated with the presence of amyloid-beta protein and neurofibrillary tangles. Despite their clinical and pathological features, there are common pathological mechanisms which occur. These include disturbances in iron metabolism (Oshiro et al., 2011), build-up α-Synuclein and Tau protein (Kim et al., 2004; Sengupta and Kayed, 2022), higher levels of oxidative stress and mitochondrial dysfunction (Alqahtani et al., 2023), reductions of noradrenergic neurons in the Locus Coeruleus and increased levels of neuroinflammation (Sakakibara et al., 2021; Zhou et al., 2021). However, despite the considerable effort in studying these two pathologies, our understanding of the mechanisms involved and the link between them remains rudimentary at best.

With this study, we investigated the commonalities of these two pathologies looking at similarities and differences in microRNA (miRNA, miR) expression patterns and pathways regulated by them. The emerging developments in the field of miRNAs has led to the investigation of their function in the nervous system physiology and pathology. High throughput sequencing experiments have reported that almost 50% of the miRNAs are expressed in the mammalian brain (Shao et al., 2010) and can play a role locally in synaptic activity, neuronal connectivity and neuroplasticity (Aksoy-Aksel et al., 2014; Ryan et al., 2015).

There is also an increased interest in miRNA roles in neurodegenerative conditions. In AD it has been reported that Aβ production involves miRNA-mediated regulation and that dysregulation of miR-29a/29b-1 alters the expression of β-secretase (BACE-1) (Hébert et al., 2008; Wang W. X. et al., 2008; Geekiyanage and Chan, 2011). MiRNAs have also been found to play an important role in PD, for example, dysregulation of miR-7 and miR-34b/c was associated with PD mitochondrial dysfunction and oxidative stress (Junn et al., 2009; Miñones-Moyano et al., 2011). Additionally, miR-133b, which plays a key role in the differentiation of dopaminergic neurones, was found to be downregulated in PD (Kim et al., 2007).

This review has the aim to identify the common features of two most common neurodegenerative diseases, AD and PD, improving our understanding of how critical biological pathways impact AD and PD and influence the neurodegenerative processes and the clinical outcomes. Common and altered AD and PD pathways can also be used to identify promising new targets for drug development as well as to identify new molecules as non-invasive biomarkers.

MiRNAs are non-coding RNAs whose function is to regulate the expression of genes via miRNA-induced silencing complex, in both physiological and pathological conditions and including neurological diseases. The ability of miRNA to regulate several physiological pathways makes it appealing in revealing new molecular mechanisms and suggesting new potential treatments. The aim of this work was to identify common miRNAs in 2 of the most important neurodegenerative diseases, potentially unveiling pathways that may be affected by both disorders and determining the link that irreversible lead to neurodegeneration.

In this study we have identified 15 common miRNAs. Five of them showed dysregulation in opposite direction in the 2 pathologies, suggesting a potential different response in the same altered pathway. Interestingly, our data showed the fatty acid (FA) biosynthesis, metabolism and degradation among the most highly significant and dysregulated pathways in both conditions. This is not surprising as brain is the second most lipid-rich organ in the body, contributing to many fundamental cellular processes, such as membrane synthesis, energy storage, signaling, and complex protein modifications (Sastry, 1985), therefore, FA homeostasis is an essential determinant of neural development, neurotransmission, and receptor activation. In AD research, cholesterol was demonstrated to contribute to the development of amyloid plaques by facilitating the formation of β-sheets (Zhou and Xu, 2012), as well as decreased concentrations of docosahexaenoic acid (DHA) were demonstrated to contribute to increased production of Amyloid β (Grimm et al., 2011).

In PD also, a disruption of FA homeostasis was reported, suggesting a role of polyunsaturated fatty acids in the formation of Lewy bodies, through the interactions of the polyunsaturated fats and the N-terminal of α-synuclein forming oligomers (Karube et al., 2008). Furthermore, a previous study supported that polyunsaturated and saturated fatty acids stabilize soluble α-synuclein oligomers (Sharon et al., 2003).

Another importantly compromised pathway that was identified by our bioinformatic analysis, is the extracellular matrix (ECM) receptor interaction pathway. ECM, which is estimated to constitute 20% of the brain, is involved in essential roles such as cell migration, proliferation and differentiation. This pathway is known to be affected in both AD and PD (Lam et al., 2019; Crapser et al., 2020) and glycosaminoglycans (GAGs), a component of the ECM, are seen in Lewy bodies and might play a role in accumulating α-synuclein by impeding its degradation and thereby facilitating Lewy bodies’ formation (Raghunathan et al., 2020).

Another pathway related to the ECM is the focal adhesion pathway which was also identified as a commonly dysregulated pathway. Focal adhesions play an essential role in cell migration, allowing cells to respond to stimuli. Under normal conditions, focal adhesion kinases (FAK) signal regulate the formation of these adhesions, and the focal adhesion molecules interact with the ECM through integrins whose activation may assist amyloid β plaque formation (Wright et al., 2007). Another study (Wang Q. et al., 2008) showed that αv integrins could also cause inhibition of long-term potentiation, disrupting synaptic plasticity and resulting in neurodegenerative effects.

Within PD, there is less evidence for the involvement of focal adhesions in pathogenesis. However, focal adhesions are critical to the neuronal interactions between other neurons and their environment. The cell adhesion pathway is hypothesized to be disrupted in PD, which affects the interaction with synaptic vesicles (Chapman, 2014). The rapid firing nature of dopaminergic neurons in the substantia nigra creates a greater demand for neurotransmitter release from the vesicles; therefore, this hypothesized dysfunction profoundly impacts neuronal communication. This process is believed to be affected by actin as actin interacts with vesicles and affects their fusion to the synaptic membrane. In addition, microtubules are thought to be involved in the trafficking of vesicles between neurons, affecting neuronal communication (Chapman, 2014). There is evidence that synaptic dysfunction occurs early in PD with decreased dopamine synthesis, storage and release; therefore, these hypothesized mechanisms could be involved in the pathogenesis of PD (Nikolaus et al., 2009). Nonetheless, further research is needed into the potential impact of the focal adhesion pathway on the pathology of PD.

Among the common list of differentially regulated miRNAs, in our pilot study we chose to validate, in a small cohort of patients, two miRNAs, let-7f-5p and miR-29b-3p and explore their potential role as non-invasive biomarkers. Let-7f-5p showed a different trend in the 2 diseases, being upregulated in AD and downregulated in PD (Hara et al., 2017; Chen et al., 2018), its target genes are involved in the cell cycle, apoptosis and cell adhesion (Ghanbari et al., 2015). However, the mechanisms through which let-7f-5p plays a role in pathogenesis are yet to be understood. An overexpression of let-7f-5p was seen in cells undergoing oxidative damage in vitro (Li K. et al., 2020). In this study, the authors using let-7f mimic have found the viability of the cells undergoing oxidative stress to improve while also decreasing apoptosis. It was discovered that AKT-2 can be repressed by let-7f, which is involved in the PI3K-Akt pathway, affecting cell proliferation and apoptosis (Li K. et al., 2020). Through this mechanism, it is speculated that the hsa-let-7f mimic can improve cell viability and reduce apoptosis.

Let-7f-5p also has a role in inflammation, targeting NLRP3 and pro-IL-1β, and repressing their expression (Tan et al., 2019). MiR-29b-3p, instead, is highly expressed in the brain and spinal cord (Smirnova et al., 2005; Hébert et al., 2008). It is involved in different mechanisms (extracellular matrix, insulin signaling, angiogenesis) (Cushing et al., 2011; Yang et al., 2014; Zhang et al., 2014) and regulates distinct cell population or pathologies (Park et al., 2009; Kwon et al., 2019) can also play crucial role during neuronal maturation, or can target BH3 protein levels in favor of neuronal degeneration (Liu et al., 2015; Huang et al., 2018). Its downregulation has been previously described in peripheral blood mononuclear cells (Villa et al., 2013), plasma (Lugli et al., 2015) and brain of subjects(Hébert et al., 2008) with AD whereby up-regulation has been seen in the cerebrospinal fluid of AD patients (Kiko et al., 2014). In addition, positive correlations were described between miR-29b concentration in serum and cortical thickness and cortical glucose metabolism (Maldonado-Lasuncion et al., 2019), which both decrease in AD. Finally, there are also studies showing the use of miR-29b as potential therapeutic agent in AD (Pereira et al., 2017).

Our data, despite the small sample size, support the existing literature, showing the downregulation of both miRNAs, let-7f and miR-29b in blood of PD patients and therefore confirming their use as potential biomarkers. On the contrary, both microRNA did not show any significant results in AD patients, although several limitations must be noted.

First of all, samples size is minimal, the number of patients that composes the validation cohorts is very low, especially for AD cohort. Moreover, AD patients were all diagnosed with an early stage of the disease and previous work showed a less strong signature of miRNA profile in the initial phase (Watson et al., 2022). Hence the large standard deviation and the consequent low statistical power for the validation studies. Therefore, a larger cohort is necessary to validate these findings.

Furthermore, there is an evident lack of age matching that may confound the interpretation of miRNA data. Therefore an age-matched control group is required for this study. The samples were extracted from whole blood, and most of the studies in the SRs reported the expression in serum/plasma. Therefore, the miRNA expression is influenced by intracellular miRNA-content. Finally, only 2 miRNAs were selected and tested in this pilot study. These two were selected on the basis of our previous results showing potential long-term implications in neurodegenerative process after a brain injury (Pietro et al., 2021).

In conclusion, this study did identify possible ways in which AD and PD share similar pathways leading to pathology, providing potential targets for future research into the disease and its treatments. A crosstalk interaction study between miRNAs and their targets related to the identified pathways is now necessary in order to propose potential area of intervention. Finally, this work was also able to show the use of miR-29b-3p as a non-invasive biomarker for PD.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

The studies involving humans were approved by the study was carried out in accordance with the recommendations of the University of Birmingham Research Ethics Committee (Ethics Ref 18-315). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

AW, LH, and VD: conceptualization and resources. BA-D, LH, and VD: methodology, formal analysis, data curation, and writing – original draft preparation. VD: validation. BW and AW: writing – review and editing. LH: project administration. LH and VD: funding acquisition. All authors contributed to the article and approved the submitted version.

This project was funded by The Midland Neuroscience Teaching and Research Fund (Charity number 313446), Queen Elizabeth Hospital Birmingham.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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