Extracellular Vesicles in Neurodegenerative Diseases

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Jinju Wang	--	2968	2023-09-07 14:24:47	\|
2	references update	Fanny Huang	Meta information modification	2968	2023-09-11 08:00:36	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijms241713161

Neurodegenerative diseases affect millions of people worldwide. The likelihood of developing a neurodegenerative disease rises dramatically as life expectancy increases. Although it has drawn significant attention, there is still a lack of proper effective treatments for neurodegenerative disease because the mechanisms of its development and progression are largely unknown. Extracellular vesicles (EVs) are small bi-lipid layer-enclosed nanosized particles in tissues and biological fluids. EVs are emerging as novel intercellular messengers and regulate a series of biological responses. Increasing evidence suggests that EVs are involved in the pathogenesis of neurodegenerative disorders.

extracellular vesicles neurodegenerative disease

1. The Potential Roles of EVs in Dementia and MCI

Dementia is a syndrome that impacts cognition, resulting in decreased function in work, lifestyle, and social contexts. Dementia may be neurodegenerative or reversible, depending on the disease or injury inducing it. However, it is important to note that most instances of dementia are a result of multiple neurological disorders or injuries. The prevalence of dementia is expected to increase to 75 million cases internationally by the conclusion of the decade, with the rising numbers attributed to aging populations. While most dementias result from protein misfolding and accumulation, vascular dementias are linked to blood loss from cerebral vasculature following brain injuries like strokes ^[1]. The general development of MCI in individuals is much less defined than dementia and its subtypes; it ranges from being neurodegenerative to not and may not even result in the onset of dementia and Alzheimer’s disease (AD).

The risk factors of dementia and mild cognitive impairment (MCI) include aging, genetics, cerebral injury, cardiovascular disease, educational attainment, and exposure to toxic materials, although risk factors typically appear in combinations in patients with dementia ^[2]. At a molecular level, dementia development is hypothesized to be in response to toxic Aβ proteins (Aβ), altered tau proteins, and/or α-synuclein (α-syn) proteins ^[3]^[4]^[5]. These proteins typically arise in one portion of the brain before gradually spreading. The systemic route in which toxic proteins manifest throughout the brain is considered when diagnosing stages of dementias such as Alzheimer’s; however, the mechanisms underlying the pattern of protein aggregation are not clear. The most closely linked yet least understood risk factor contributing to dementia is having two APoE4 alleles, which only appears in a small fraction of individuals. APoE4 often exacerbates other risk factors such as cardiovascular and neurological diseases; the gene and the diseases simultaneously result in the upregulation of toxic proteins and cerebral inflammation ^[6].

Within the past decade, research has turned to EVs to uncover the mechanistic route of dementia and its comorbidities’ onset and progression. EVs may have either negative or positive effects depending upon the cells that they originate from and may have roles in the advancement of diseases by dispersing toxic cargoes ^[7]. It is further established that all cells of the central nervous system, as well as endothelial cells, deposit EVs that participate in the body’s inter-organ communication ^[8]^[9]. Current research aims to identify whether EVs secreted by cells within the brain can transmit toxic RNAs, lipids, or proteins and the mechanisms in which this may occur. Increasing evidence has uncovered that EVs carry toxic proteins that contribute to the development of dementias under numerous disease conditions, such as AD and Parkinson’s disease (PD) ^[10]. It has been also proposed that EVs such as EXs can transmit miRNA and lipids within the brain, promoting cell death and inflammation, especially during AD and PD-induced dementia ^[11].

Endothelial cells have been suggested as possible contributors to disease spread and exacerbation due to their respective roles in performing as sites of inflammation and protein accumulation in dementia syndrome ^[9]. One study has linked cerebral endothelial-cell-derived small extracellular vesicles (CEC-sEVs) to causing cognitive dysfunction in diabetic conditions; CEC-sEVs extracted from healthy mice, as expected, reduced cognitive decline when administered to diabetic mice ^[12]. Recently, another report revealed that microglia-derived vesicles were found in higher concentrations in frail patients with MCI compared with non-frail ones, pointing to their participation in cognitive decline. These microglia-derived vesicles were also factors in creating neuronal damage. The article concludes by stating that microglia dysfunction is common in various cognitive diseases and expedites the formation and release of Aβ proteins, which may be via EVs ^[13].

Other forms of dementia, such as vascular dementia, are also studied alongside AD and MCI because of their common appearances as comorbidities. The risk factors for vascular dementia differ slightly; while they still include aging and genetics, a higher significance is placed upon physical, preventable health and lifestyle choices, such as hyperglycemia, hypertension, and obesity. A study examining diabetes as a risk factor for vascular dementia notes that the efflux of proteins such as hsp60 from neuron EXs is elevated in diabetic individuals, resulting in astrocytes taking up the hsp60 and spreading oxidative stress and, hence, inflammation throughout the brain ^[14]. This inflammation occurs by damaging neurons and glial cells.

Frontotemporal lobar degeneration (FTLD) is another type of dementia, in which neurons in the frontal and temporal lobes of the brain are destroyed by the accumulation of TAR DNA binding protein-43 (TDP-43), resulting in extensive memory and function loss. Those with frontal lobar degeneration-dependent dementia are significantly more likely to feature mutations in the progranulin gene (GRN), and studies have concluded that EVs from neural, astrocytic, and microglial cells can accumulate and spread toxic TDP-43 ^[15]^[16]. Clinical studies have found that EXs can transmit TDP-43 in patients with FTLD in a prion-like manner, which then leads to neuronal death ^[17]. Other groups have indicated that TDP-43 was detected in EXs released from neuroblasts and primary neurons ^[18].

Outside of disease progression, EVs have the potential to serve as biomarkers. Upadhya et al. have demonstrated that in various neurocognitive diseases, circulating EVs released by astrocytes may play a role in identifying the severity of the condition and, in non-degenerative cases, provide a route to measure the stages of healing ^[19]. The development of dementia from MCI to dementia can be examined closer using proteomic biomarkers such as hsp1A, puromycin-sensitive aminopeptidase, and prostaglandin F2 receptor negative regulator, as per Muraoka and colleagues ^[20]. In terms of the Aβ hypothesis, it has also been suggested that plasma EVs can indicate how much MCI has advanced ^[21]. For FTLD, the TDP-43 levels in astrocyte EVs isolated from plasma can serve as a novel biomarker ^[16]. EXs in diseased individuals are prone to containing higher concentrations of neurofilament light chain levels, meaning that EXs could be used to anticipate FTLD onset ^[22]. Sproviero et al. observed distinct differences in mRNA cargoes in EVs sourced from AD, PD, and FTLD samples and those from control samples. These mRNAs are related to serine arginine-rich protein families, kinase genes, splicing, and heat shock proteins ^[23]. Another study found that EV concentrations increased and the average size decreased in patients with AD, DLB, and FTLD ^[24]. For dementia with Lewy bodies (DLB), biomarkers may include the RNA expression levels in small EVs circulating in plasma or altered protein levels in plasma EVs, such as gelsolin and butyrylcholinesterase ^[25]^[26]^[27]. EVs in the cerebral spinal fluid of DLB subjects may also be involved in abnormal ceramide concentrations and metabolism ^[28].

2. The Potential Roles of EVs in Alzheimer’s Disease

AD is the most common and well-known form of dementia that has been well studied yet still not fully understood. AD coincides with vascular dementia in most cases, indicating a link between AD-induced cognitive decline and cardiovascular disease ^[2]. Despite having such a high prevalence, no pharmaceutical treatments have been made available in the market for AD. Some have suggested that the lack of medicines for those suffering from AD can be attributed to a failure to address amyloid/tau accumulation simultaneously with cerebrovascular diseases ^[4].

Previously, it was supposed that contact between cells in the brain was responsible for the progress of AD ^[29]. In recent years, many laboratories have begun to consider EVs as a potential mode of transportation for toxic biomaterials within the brain ^[30]. Endothelial cells, for instance, which are important components of the blood–brain barrier (BBB), have been noted to produce EVs containing Aβ proteins ^[9]. These EVs containing toxic Aβ proteins across the BBB effectively reduce the production of neurons from neuron progenitor cells by inducing mitochondrial dysfunction and oxidative stress. This causes a cyclic pattern in which increasing Aβ levels damage the BBB, forming a dysfunctional influx/efflux of EXs that also contain Aβ, driving neurodegeneration.

The body of research on the spread of AD via EVs generally focuses on EVs of glial or neuronal origin in AD progression ^[8]^[31]. This is supported by work that indicates that most EV particles shift from neurons to glial cells and that Aβ and tau protein concentrations in EVs increase as AD develops ^[32]^[33]. Muraoka and colleagues reported that brain-derived EVs carry a higher level of signature proteins Aβ and tau and glial-specific molecules such as ANXA5, VGF, GPM6A, and ACTZ in AD patients compared with control subjects ^[32]. The combination of Aβ, tau, and brain-cell-specific proteins, including ANAX5, VGF, GPM6A, or ACTZ, may serve as potential biomarker candidates in AD patient body fluid samples. Asai et al. also found that reduced microglial cell concentrations and microglial EX production in the brain are related to diminished tau proteins in AD ^[34]. In inflammatory conditions, microglia can also communicate signals with each other, resulting in lipids found in both microglia intracellularly and released via MVs extracellularly to initiate the conversion of Aβ from normal insoluble forms to toxic soluble versions ^[31]. Additionally, the spreading of tau via EXs is also shown to have occurred between neurons and microglia ^[35]. Microglia-derived MVs displayed neurotoxicity to microglia and cortical neurons by trafficking neurotoxic Aβ proteins ^[31]^[36]. Some studies have discovered that astrocyte EVs were increased in cerebrospinal fluid in AD relative to MCI patients and controls, further pointing to the idea that glial cells serve as the mode of AD proliferation ^[20]. Another finding that highlights the potential importance of glial cells in the spread is that because they serve as the primary phagocytic cells within the brain, they have an amplified ability to both phagocytize and excrete vesicles compared with neurons ^[34]. Nevertheless, this is in direct contrast to studies that propose protein distribution between neurons in a prion-like fashion without glial cells as mediators ^[37]. When proteins such as tau are released via EXs, they can induce constitutive tau proteins to convert to their toxic forms ^[38]^[39]. In studies where neurons distribute EVs to each other, microglia have been observed to serve as a means to degrade EXs rather than releasing them ^[40].

Both astrocytes and neurons produce EVs with increased tau and Aβ levels in AD conditions ^[41]^[42]^[43]. Therefore, a biomarker for AD could be established by measuring Aβ and tau protein concentrations in EVs isolated from CSF and blood ^[44]^[45]. It has also been observed that EXs released from astrocytes may have increased levels of inflammatory proteins that can be utilized as biomarkers ^[46]. Proteins also isolated from EXs produced by neurons include Aβ and p-tau proteins and have the potential to serve as biomarkers ^[45]^[47]. Specifically, increasing levels of toxic proteins in neuron EVs correspond to the progression of AD throughout the brain ^[48]. mRNA and miRNA are also cargoes found in neuron-derived EXs that could be utilized as biomarkers of cognitive impairment in AD ^[49]. Outside of astrocytes and neurons, miRNAs, inflammatory factors, and toxic proteins also found in microglia, released EXs can also serve as biomarkers ^[34]^[50]. Jia et al. conducted a multicenter study with four independent datasets and found that a panel of miRs was changed in subjects with AD and could detect preclinical AD five to seven years before the onset of cognitive impairment ^[51]. Markers such as Alix also indicate increased release of EXs around diseased areas of the brain ^[30]. There is currently an abundance of research being conducted on EVs as novel biomarkers for AD, exploring more specificities of the relationship than with other neurocognitive disorders.

3. The Potential Roles of EVs in Parkinson’s Disease

While, like AD, PD can result in dementia and cognitive decline, PD also presents itself with physical challenges like bradykinesia and tremors. This indicates the primary manifestation of the disease is not in the entorhinal cortex or hippocampus but in the substantia nigra responsible for one’s movement ^[52]. PD also is associated with Aβ, tau, and neuron-damaging α-syn proteins that form Lewy bodies characteristic of PD and LBD ^[53].

Recent studies have indicated that EVs such as EXs can serve as transporters of α-syn oligomeric proteins throughout neurons in the brain, expediting the spread and growth of the Lewy bodies ^[54]. These findings have been supported extensively by studies that indicate that neuron-based EXs containing α-syn oligomers are more likely to be taken up by neurons than those without α-syn proteins ^[55]^[56]. However, like with AD, it is not universally accepted that the transmission of EVs occurs neuron to neuron, and some have shown that EXs can be released by glial cells before being absorbed by neurons ^[57]. Secretion of the toxic α-syn proteins can be induced by high intracellular concentrations of calcium, but the pathological pathway has not been completely elucidated ^[58]^[59]. In diabetes, the negative impact of EVs on those with PD is increased due to the EX-based transportation of α-syn from the pancreas to neurons ^[60]. Aside from proteins, research groups have shown that miRNA such as novel miR-44438 in EVs reduces α-syn disposal by neurons, resulting in their buildup within neurons ^[61]. Other RNAs, such as miR-34a, which are packaged into EXs and secreted by astrocytes, promote neurotoxicity and inflammation in PD by increasing the concentration of toxic molecules and inflammatory proteins ^[57]^[62]. Clinical studies reported that specific miRs (hsa-miR-23a-3p, hsa-miR-126-3p, hsa-let-7i-5p, and hsa-miR-151a-3p) significantly decreased in AD with respect to controls ^[63].

EVs can also serve as biomarkers within the context of PD. Bloomer and colleagues identified neuron EXs isolated from plasma as potential biomarkers because they can feature different levels of α-syn oligomers, Aβ, p-tau, and insulin signaling-related proteins ^[64]. Further, it has been shown that elevated α-syn levels in neuron EXs found in serum precedes fully developed PD, demonstrating novel ways that they could serve as biomarkers ^[65]. PD, like AD, also includes altered exosomal cargo profiles, including altered levels of miRs (miR-153, miR-409-3p, miR-10a-5p, and let-7g-3p), mRNAs of the amyloid precursor protein, α-syn, Tau, neurofilament light gene, DJ-1/PARK7, and long non-coding RNAs (RP11-462G22.1 and PCA3) in EXs in cerebral spinal fluid ^[66], suggesting that cerebral spinal fluid exosomal RNA molecules could serve as biomarkers in regard to specificity and sensitivity in differentiating PD from healthy controls.

4. The Promise of EVs in Treating Neurodegenerative Diseases

EVs can also function as a novel therapeutic tool for neurodegenerative diseases given that they can penetrate through the BBB and target the brain. On a general level, Raghav and colleagues have systematically reviewed sixty articles on how EVs may serve as therapeutics in neurodegenerative diseases; studies have stated that patient-specific or parent-cell-specific EVs can be used to catalyze regeneration post-damage, transport beneficial siRNAs and pharmaceuticals, and restore neurological functions ^[67]. Alvarez-Erviti et al. engineered EXs to express the central-nervous-system-specific rabies viral glycoprotein peptide and found these EXs exhibited the capability of delivering siRNA to neurons, microglia, and oligodendrocytes, demonstrating a significant reduction of Aβ deposits in the mouse brain ^[68]. As demonstrated by Yuyama et al., EXs can act as scavengers of extracellular Aβ by trapping the Aβ on surface glycosphingolipids and transporting it into microglia in the AD mouse brain ^[69]. Xia and colleagues have also conducted a more narrow review of the therapeutic effects of specifically EVs produced by transplanted stem cells, which may reduce Aβ and α-syn deposition, apoptosis, and oxidative stress in addition to promoting angiogenesis and cell regeneration ^[70]. More specifically, mesenchymal stem-cell-derived EVs can convey specific cargo such as miR-29c-3p to neurons, which then inhibits BACE1 expression while activating the Wnt/β-catenin pathway ^[71]. EVs released from neural stem cells also exhibit neuroprotective effects, restore fear extinction memory consolidation, and reduce anxiety-related behaviors of the 5xFAD accelerated transgenic mouse model of AD ^[72]. Cui and colleagues revealed that EXs derived from hypoxia-preconditioned mesenchymal stromal cells can rescue cognitive impairment in the Alzheimer APP/PS1 mouse model ^[73].

An increasing number of studies are turning to implementing exercise intervened EVs to see if they could be another mechanism through which exercise can produce biological changes in the central nervous system. Fruhbeis et al. reported that exhaustive cycle and treadmill exercise raised EVs secretion into the circulation immediately post-exercise, which returns to baseline after 90 min ^[74]^[75]. The researchers' group has demonstrated that moderate treadmill exercise intervention (10 m/min for 60 min for 8 weeks) regulates the functions of bone marrow endothelial progenitor-cell-derived EXs in C57BL/6 mice ^[76]. Furthermore, researchers' recent study revealed that the exosomal communication between endothelial progenitor cells and brain cells is compromised in hypertensive conditions ^[77]. Whether the altered exosomal communication is involved in the progression of hypertension-associated neurodegenerative diseases is largely unknown. Additionally, proteins including CD36, flotillin-1, alpha-sarcoglycan, HSP72, and Aβ have been observed in exercise-induced EVs ^[78]. However, the biological functions of these proteins are currently unclear.

EVs can also serve as vehicles to carry therapeutic molecules to treat cognitive decline. Proteins such as catalase can be packaged into EXs derived from macrophages and monocytes, which can be taken up by neurons to reduce oxidative stress in PD ^[79]. Studies have also found that stimulating astrocytes via inflammation and oxidative stress may induce them to release EVs, which can promote recovery and might be used to regenerate cells post-dementia injury ^[19]. Other research groups also loaded glial-cell-derived neurotrophic factors into EXs and introduced them to a monkey PD model. They found that these engineered EXs exhibited a strong neuroprotective effect ^[80]. All these findings indicate that EXs are promising carriers for delivering drugs to the central nervous system, but more research is needed in the future on the delivery of therapeutic drugs such as siRNAs and miRNAs and on the development of instruments or methods for engineering EXs.

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