Extracellular vesicles in Alzheimer's and Parkinson's disease : small entities with large consequences

Alzheimer's disease (AD) and Parkinson's disease (PD) are incurable, devastating neurodegenerative disorders characterized by the formation and spreading of protein aggregates throughout the brain. Although the exact spreading mechanism is not completely understood, extracellular vesicles (EVs) have been proposed as potential contributors. Indeed, EVs have emerged as potential carriers of disease-associated proteins and are therefore thought to play an important role in disease progression, although some beneficial functions have also been attributed to them. EVs can be isolated from a variety of sources, including biofluids, and the analysis of their content can provide a snapshot of ongoing pathological changes in the brain. This underlines their potential as biomarker candidates which is of specific relevance in AD and PD where symptoms only arise after considerable and irreversible neuronal damage has already occurred. In this review, we discuss the known beneficial and detrimental functions of EVs in AD and PD and we highlight their promising potential to be used as biomarkers in both diseases

Free complement and complement containing extracellular vesicles as potential biomarkers for neuroinflammatory and neurodegenerative disorders

The complement system is implicated in a broad range of neuroinflammatory disorders such as Alzheimer’s disease (AD) and multiple sclerosis (MS). Consequently, measuring complement levels in biofluids could serve as a potential biomarker for these diseases. Indeed, complement levels are shown to be altered in patients compared to controls, and some studies reported a correlation between the level of free complement in biofluids and disease progression, severity or the response to therapeutics. Overall, they are not (yet) suitable as a diagnostic tool due to heterogeneity of reported results. Moreover, measurement of free complement proteins has the disadvantage that information on their origin is lost, which might be of value in a multi-parameter approach for disease prediction and stratification. In light of this, extracellular vesicles (EVs) could provide a platform to improve the diagnostic power of complement proteins. EVs are nanosized double membrane particles that are secreted by essentially every cell type and resemble the (status of the) cell of origin. Interestingly, EVs can contain complement proteins, while the cellular origin can still be determined by the presence of EV surface markers. In this review, we summarize the current knowledge and future opportunities on the use of free and EV-associated complement proteins as biomarkers for neuroinflammatory and neurodegenerative disorders

Counteracting the effects of TNF receptor-1 has therapeutic potential in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia, and neuroinflammation is an important hallmark of the pathogenesis. Tumor necrosis factor (TNF) might be detrimental in AD, though the results coming from clinical trials on anti-TNF inhibitors are inconclusive. TNFR1, one of the TNF signaling receptors, contributes to the pathogenesis of AD by mediating neuronal cell death. The blood-cerebrospinal fluid (CSF) barrier consists of a monolayer of choroid plexus epithelial (CPE) cells, and AD is associated with changes in CPE cell morphology. Here, we report that TNF is the main inflammatory upstream mediator in choroid plexus tissue in AD patients. This was confirmed in two murine AD models: transgenic APP/PS1 mice and intracerebroventricular (icv) AβO injection. TNFR1 contributes to the morphological damage of CPE cells in AD, and TNFR1 abrogation reduces brain inflammation and prevents blood-CSF barrier impairment. In APP/PS1 transgenic mice, TNFR1 deficiency ameliorated amyloidosis. Ultimately, genetic and pharmacological blockage of TNFR1 rescued from the induced cognitive impairments. Our data indicate that TNFR1 is a promising therapeutic target for AD treatment

Extracellular vesicles : a double-edged sword in sepsis

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to an infection. Several studies on mouse and patient sepsis samples have revealed that the level of extracellular vesicles (EVs) in the blood is altered compared to healthy controls, but the different functions of EVs during sepsis pathology are not yet completely understood. Sepsis EVs are described as modulators of inflammation, lymphocyte apoptosis, coagulation and organ dysfunction. Furthermore, EVs can influence clinical outcome and it is suggested that EVs can predict survival. Both detrimental and beneficial roles for EVs have been described in sepsis, depending on the EV cellular source and the disease phase during which the EVs are studied. In this review, we summarize the current knowledge of EV sources and functions during sepsis pathology based on in vitro and mouse models, as well as patient samples

Special delEVery : extracellular vesicles as promising delivery platform to the brain

The treatment of central nervous system (CNS) pathologies is severely hampered by the presence of tightly regulated CNS barriers that restrict drug delivery to the brain. An increasing amount of data suggests that extracellular vesicles (EVs), i.e., membrane derived vesicles that inherently protect and transfer biological cargoes between cells, naturally cross the CNS barriers. Moreover, EVs can be engineered with targeting ligands to obtain enriched tissue targeting and delivery capacities. In this review, we provide a detailed overview of the literature describing a natural and engineered CNS targeting and therapeutic efficiency of different cell type derived EVs. Hereby, we specifically focus on peripheral administration routes in a broad range of CNS diseases. Furthermore, we underline the potential of research aimed at elucidating the vesicular transport mechanisms across the different CNS barriers. Finally, we elaborate on the practical considerations towards the application of EVs as a brain drug delivery system

Biomarker and therapeutic potential of peripheral extracellular vesicles in Alzheimer's disease

Extracellular vesicles (EVs) are cell-derived nanoparticles with an important role in intercellular commu-nication, even across brain barriers. The bidirectional brain-barrier crossing capacity of EVs is supported by research identifying neuronal markers in peripheral EVs, as well as the brain delivery of peripherally administered EVs. In addition, EVs are reflective of their cellular origin, underlining their biomarker and therapeutic potential when released by diseased and regenerative cells, respectively. Both characteristics are of interest in Alzheimer's disease (AD) where the current biomarker profile is solely based on brain -centered readouts and effective therapeutic options are lacking. In this review, we elaborate on the role of peripheral EVs in AD. We focus on bulk EVs and specific EV subpopulations including bacterial EVs (bEVs) and neuronal-derived EVs (nEVs), which have mainly been studied from a biomarker perspective. Furthermore, we highlight the therapeutic potential of peripherally administered EVs whereby research has centered around stem cell derived EVs.(c) 2022 Published by Elsevier B.V

Free complement and complement containing extracellular vesicles as potential biomarkers for neuroinflammatory and neurodegenerative disorders

The complement system is implicated in a broad range of neuroinflammatory disorders such as Alzheimer's disease (AD) and multiple sclerosis (MS). Consequently, measuring complement levels in biofluids could serve as a potential biomarker for these diseases. Indeed, complement levels are shown to be altered in patients compared to controls, and some studies reported a correlation between the level of free complement in biofluids and disease progression, severity or the response to therapeutics. Overall, they are not (yet) suitable as a diagnostic tool due to heterogeneity of reported results. Moreover, measurement of free complement proteins has the disadvantage that information on their origin is lost, which might be of value in a multi-parameter approach for disease prediction and stratification. In light of this, extracellular vesicles (EVs) could provide a platform to improve the diagnostic power of complement proteins. EVs are nanosized double membrane particles that are secreted by essentially every cell type and resemble the (status of the) cell of origin. Interestingly, EVs can contain complement proteins, while the cellular origin can still be determined by the presence of EV surface markers. In this review, we summarize the current knowledge and future opportunities on the use of free and EV-associated complement proteins as biomarkers for neuroinflammatory and neurodegenerative disorders

Caloric restriction: beneficial effects on brain aging and Alzheimer's disease

Dietary interventions such as caloric restriction (CR) extend lifespan and health span. Recent data from animal and human studies indicate that CR slows down the aging process, benefits general health, and improves memory performance. Caloric restriction also retards and slows down the progression of different age-related diseases, such as Alzheimer's disease. However, the specific molecular basis of these effects remains unclear. A better understanding of the pathways underlying these effects could pave the way to novel preventive or therapeutic strategies. In this review, we will discuss the mechanisms and effects of CR on aging and Alzheimer's disease. A potential alternative to CR as a lifestyle modification is the use of CR mimetics. These compounds mimic the biochemical and functional effects of CR without the need to reduce energy intake. We discuss the effect of two of the most investigated mimetics, resveratrol and rapamycin, on aging and their potential as Alzheimer's disease therapeutics. However, additional research will be needed to determine the safety, efficacy, and usability of CR and its mimetics before a general recommendation can be proposed to implement them