brain fingerprinting blotted science tab

The presence of proteins and the potential transfer of proteins via EVs to recipient cells has been hypothesized to be involved in spreading pathological factors in in vitro models including Aβ, Tau and prions.

Upon fusion of the MVB, the ILVs are released into the extracellular environment as exosomes and loaded with specific proteomic and genomic cargo packaged from the parental cell. The most intensely studied subtype of EVs are exosomes or “small EVs“ which are approximately 50–200 nm in size, enveloped by a lipid bi-layer and formed by the inward invagination of the late endosomal membrane to form the multi-vesicular body (MVB) containing intraluminal vesicles (ILVs).

In physiological and neurodegenerative disturbances, EVs are known to modulate the cross talk between neurons and non-neuronal cell types such as microglia, astrocytes and dendrocytes. Furthermore, the deregulation of miRNA expression can also spread via “horizontal” RNA transfer through EVs to act in conjunction with proteins leading to changes in mRNA and consequently destruction of biological functions within neuron and glia cells of the brain. To further enhance sensitivity and detection at pre-clinical stage, miRNA can be isolated from enriched preparations of extracellular vesicles (EVs) from the brain to study the molecular events in the development of AD. miRNA is highly present in the brain compared to other tissues and early studies identified brain-enriched miRNA including those associated with AD detected as early as Braak stage III. Generally, transcriptional deregulation can be detected earlier than the presence of pathological hallmarks and may be considered as the first indication of phenotypic changes in the brain. Neurofibrillary tangles appear at Braak stage I and II within the transentorhinal region and entorhinal region during the pre-clinical stage of AD, stage III and IV in the temporo-occipital cortex and temporal cortex on the appearance of symptoms followed by stage V and VI in the occipital cortex and neocortex. These neuropathological changes occur at early stages before the onset of dementia which is difficult to diagnose, thus highlighting a need to identify biomarkers that can inform early changes in the brain. Staging of Alzheimer’s disease (AD) related pathology and lesions, in particular amyloid-β (Aβ) plaques and neurofibrillary tangles, occurs in a predictable sequence across interconnected regions of the brain, known as Braak staging. Overall, our study provides the first interrogation of the small RNA contents in brain-derived EVs and how they could be used to understand the early pathological changes in Alzheimer’s disease which will benefit the development of an early diagnostic blood test. These results provide a blueprint into the biological pathways potentially effected during disease that may be assisted by brain-derived EV RNA horizontal transfer.We also correlated the miRNA changes in the brain with those detected in peripheral EVs collected from serum of Alzheimer’s disease patients ( n = 23, and healthy controls, n = 23) and revealed a panel of miRNA that could be used as a liquid brain biopsy. RNA species from brain-derived EVs were correlated with miRNA profiles obtained from matching total brain homogenate. Brain-derived EVs were found to contain an upregulation of disease-associated miRNA. Here, we analysed the small RNA content, in particular, miRNA, contained in brain-derived EVs isolated from the frontal cortex of Alzheimer’s subjects ( n = 8) and neurological control subjects ( n = 9). Transcriptomic deregulation of miRNA expression can spread via “horizontal” RNA transfer through extracellular vesicles (EVs) to act in conjunction with proteins, leading to changes in mRNA, which can provide early signals to indicate forthcoming neuropathological changes in the brain. Alzheimer’s disease is a progressive neurodegenerative disorder, with the strongest disease-associated changes observed at clinical or end-stage disease.

Brain fingerprinting blotted science tab