Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease (original) (raw)
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CNS Drugs
Disturbed proteostasis as reflected by a massive accumulation of misfolded protein aggregates is a central feature in Alzheimer's disease. Proteostatic disturbances may be caused by a shift in protein production and clearance. Whereas rare genetic causes of the disease affect the production side, sporadic cases appear to be directed by dysfunction in protein clearance. This review focusses on the involvement of lysosome-mediated clearance. Autophagy is a degradational system where intracellular components are degraded by lysosomal organelles. In addition, "outside-to-inside" trafficking through the endosomes converges with the autolysosomal pathway, thereby bringing together intracellular and extracellular components. Recent findings demonstrate that disturbance in the endo-and autolysosomal pathway induces "inside-to-outside" communication via induction of unconventional secretion, which may bear relevance to the spreading of disease pathology through the brain. The involvement of these pathways in the pathogenesis of the disease is discussed with an outlook to the opportunities it provides for diagnostics as well as therapeutic interventions.
Alzheimer's & Dementia, 2014
Background: Proteins pathogenic in Alzheimer's disease (AD) were extracted from neurally derived blood exosomes and quantified to develop biomarkers for the staging of sporadic AD. Methods: Blood exosomes obtained at one time-point from patients with AD (n 5 57) or frontotemporal dementia (FTD) (n 5 16), and at two time-points from others (n 5 24) when cognitively normal and 1 to 10 years later when diagnosed with AD were enriched for neural sources by immunoabsorption. AD-pathogenic exosomal proteins were extracted and quantified by enzyme-linked immunosorbent assays. Results: Mean exosomal levels of total tau, P-T181-tau, P-S396-tau, and amyloid b 1-42 (Ab1-42) for AD and levels of P-T181-tau and Ab1-42 for FTD were significantly higher than for case-controls.
Plasma neuronal exosomal levels of Alzheimer's disease biomarkers in normal aging
Annals of clinical and translational neurology, 2016
Plasma neuronal exosomal levels of pathogenic Alzheimer's disease (AD) proteins, cellular survival factors, and lysosomal proteins distinguish AD patients from control subjects, but changes in these exosomal proteins associated with normal aging have not been described for cognitively intact subjects. Plasma neuronal exosomal levels of P-T181-tau, P-S396-tau, Aβ 1-42, cathepsin D, repressor element 1-silencing transcription factor, and neurogranin were quantified longitudinally in cognitively intact older adults using two samples collected at 3- to 11-year intervals. Except for P-S396-tau, exosomal protein levels changed significantly with aging, but were largely outside the range observed in AD patients.
Plasma Neuronal Exosomal Levels of Alzheimer\u27s Disease Biomarkers in Normal Aging
2016
Plasma neuronal exosomal levels of pathogenic Alzheimer\u27s disease (AD) proteins, cellular survival factors, and lysosomal proteins distinguish AD patients from control subjects, but changes in these exosomal proteins associated with normal aging have not been described for cognitively intact subjects. Plasma neuronal exosomal levels of P-T181-tau, P-S396-tau, Aβ1-42, cathepsin D, repressor element 1-silencing transcription factor, and neurogranin were quantified longitudinally in cognitively intact older adults using two samples collected at 3- to 11-year intervals. Except for P-S396-tau, exosomal protein levels changed significantly with aging, but were largely outside the range observed in AD patients
Exosomes as possible spread factor and potential biomarkers in Alzheimer's disease: current concepts
Biomarkers in Medicine, 2018
Increasing evidence points that important factors during development/spread of Alzheimer's disease in brain tissue are small extracellular vesicles, called exosomes. Exosomes comprise disease-related biomolecules such as the amyloid protein precursor, β-amyloid peptide and tau protein. Exosomes are hypothesized to facilitate the spread of β-amyloid peptide and tau protein from their cells of origin (e.g., neurons) to the extracellular space and to recipient cells to alter their phenotype and function. The roles of exosomes carry a rich biomolecules cargo in physiology and pathology is poorly understood. In this review, we will consider new information about the role of exosomes in Alzheimer's disease spreading and progression and underline their possible usefulness as the future diagnostic antemortem biomarkers in this devastating disorder.
Endo-lysosomal and autophagic dysfunction: a driving factor in Alzheimer's disease?
Journal of Neurochemistry
Alzheimer's disease (AD) is the most common cause of dementia, and its prevalence will increase significantly in the coming decades. Although important progress has been made, fundamental pathogenic mechanisms as well as most hereditary contributions to the sporadic form of the disease remain unknown. In this review, we examine the now substantial links between AD pathogenesis and lysosomal biology. The lysosome hydrolyses and processes cargo delivered by multiple pathways, including endocytosis and autophagy. The endo-lysosomal and autophagic networks are central to clearance of cellular macromolecules, which is important given there is a deficit in clearance of amyloid-b in AD. Numerous studies show prominent lysosomal dysfunction in AD, including perturbed trafficking of lysosomal enzymes and accumulation of the same substrates that accumulate in lysosomal storage disorders. Examination of the brain in lysosomal storage disorders shows the accumulation of amyloid precursor protein metabolites, which further links lysosomal dysfunction with AD. This and other evidence leads us to hypothesise that genetic variation in lysosomal genes modifies the disease course of sporadic AD.
The role of exosomes in the processing of proteins associated with neurodegenerative diseases
European Biophysics Journal With Biophysics Letters, 2008
Exosomes are small membranous vesicles secreted by a number of cell types and can be isolated from conditioned cell media or bodily fluids such as urine and plasma. Exosome biogenesis involves the inward budding of multivesicular bodies (MVB) to form intraluminal vesicles (ILV). When fused with the plasma membrane, the MVB releases the vesicles into the extracellular environment as exosomes. Proposed functions of these vesicles include roles in cell–cell signalling, removal of unwanted proteins, and the transfer of pathogens between cells, such as HIV-1. Another such pathogen which exploits this pathway is the prion, the infectious particle responsible for the transmissible neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD) of humans or bovine spongiform encephalopathy (BSE) of cattle. Interestingly, this work is mirrored by studies on another protein involved in neurodegenerative disease, the amyloid precursor protein (APP) which is associated with Alzheimer’s disease (AD). Recent work has found APP proteolytic fragments in association with exosomes, suggesting a common pathway previously unknown for proteins associated with neurodegenerative diseases. This review will be discussing the current literature regarding the role of exosomes in secretion of the proteins, PrP and APP, and the subsequent implications for neurodegenerative disease.
Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study
Journal of neuropathology and experimental neurology, 2005
The accumulation of lysosomes and their hydrolases within neurons is a well-established neuropathologic feature of Alzheimer disease (AD). Here we show that lysosomal pathology in AD brain involves extensive alterations of macroautophagy, an inducible pathway for the turnover of intracellular constituents, including organelles. Using immunogold labeling with compartmental markers and electron microscopy on neocortical biopsies from AD brain, we unequivocally identified autophagosomes and other prelysosomal autophagic vacuoles (AVs), which were morphologically and biochemically similar to AVs highly purified from mouse liver. AVs were uncommon in brains devoid of AD pathology but were abundant in AD brains particularly, within neuritic processes, including synaptic terminals. In dystrophic neurites, autophagosomes, multivesicular bodies, multilamellar bodies, and cathepsin-containing autophagolysosomes were the predominant organelles and accumulated in large numbers. These compartmen...
International Journal of Molecular Sciences
Exosomes (EXOs) were given attention as an extracellular vesicle (EV) with a pivotal pathophysiological role in the development of certain neurodegenerative disorders (NDD), such as Parkinson’s and Alzheimer’s disease (AD). EXOs have shown the potential to carry pathological and therapeutic cargo; thus, researchers have harnessed EXOs in drug delivery applications. EXOs have shown low immunogenicity as natural drug delivery vehicles, thus ensuring efficient drug delivery without causing significant adverse reactions. Recently, EXOs provided potential drug delivery opportunities in AD and promising future clinical applications with the diagnosis of NDD and were studied for their usefulness in disease detection and prediction prior to the emergence of symptoms. In the future, the microfluidics technique will play an essential role in isolating and detecting EXOs to diagnose AD before the development of advanced symptoms. This review is not reiterative literature but will discuss why E...
Alzheimer's disease beta-amyloid peptides are released in association with exosomes
Proceedings of the National Academy of Sciences, 2006
Although the exact etiology of Alzheimer's disease (AD) is a topic of debate, the consensus is that the accumulation of -amyloid (A) peptides in the senile plaques is one of the hallmarks of the progression of the disease. The A peptide is formed by the amyloidogenic cleavage of the amyloid precursor protein (APP) by and ␥-secretases. The endocytic system has been implicated in the cleavages leading to the formation of A. However, the identity of the intracellular compartment where the amyloidogenic secretases cleave and the mechanism by which the intracellularly generated A is released into the extracellular milieu are not clear. Here, we show that -cleavage occurs in early endosomes followed by routing of A to multivesicular bodies (MVBs) in HeLa and N2a cells. Subsequently, a minute fraction of A peptides can be secreted from the cells in association with exosomes, intraluminal vesicles of MVBs that are released into the extracellular space as a result of fusion of MVBs with the plasma membrane. Exosomal proteins were found to accumulate in the plaques of AD patient brains, suggesting a role in the pathogenesis of AD. multivesicular bodies ͉ rafts ͉ amyloid precursor protein ͉ -secretase ͉ endocytosis A lzheimer's disease (AD) is a late-onset neurological disorder with progressive loss of memory and cognitive abilities as a result of excessive neurodegeneration (1). AD is characterized by extracellular aggregates of -amyloid (A) peptides known as amyloid plaques (2). The A peptide is derived from the sequential processing of the amyloid precursor protein (APP) by and ␥-secretases. -secretase [(-APP cleaving enzyme (BACE)] is a type-1 transmembrane aspartyl protease and is mainly localized to endosomes, lysosomes and the trans-Golgi network (3). ␥-Secretase is a multicomponent complex that is composed of presenilin-1͞presenilin-2, nicastrin, Aph-1, and PEN-2 (4) and is localized to the early secretory (5, 6) and the endocytic compartments (7, 8). Nonamyloidogenic processing of APP involves ␣-secretase that cleaves APP inside the A region, giving rise to the ␣-cleaved ectodomain, thus precluding the formation of A (9). Hence, the availability of APP to either ␣or -secretase determines whether A peptide will be generated. Lateral organization of membranes (10) and subcellular localization (11, 12) of the substrate and the secretases have been documented to regulate A generation. Recent work suggests that -secretase associates with lipid rafts, liquid-ordered domains in the membrane , and that integrity of raft domains is required for -cleavage of APP to occur (ref. 10; see, however, ref. 15). ␣-Cleavage, in contrast, occurs outside raft domains (10). The ␥-secretase complex is also raft-associated (16); hence, amyloidogenic processing of APP could occur in clustered raft domains to generate A (10). Inhibition of endocytosis reduces -cleavage but not ␣-cleavage, suggesting that -cleavage mainly occurs in endosomes . Accumulation of A peptides in extracellular plaques requires the release of A peptides from the cell. An intriguing question is how the intracellularly generated, fairly hydrophobic A peptide is released into the extracellular space. Here we show that -cleavage occurs in a specific subset of endosomes and that a fraction of A peptides is found in multivesicular bodies (MVBs) and is released in association with exosomes. Upon fusion of MVBs with the plasma membrane, the intraluminal vesicles of MVBs are released into the extracellular milieu as exosomes. These vesicles are enriched in raft lipids and proteins and are implicated in various functions, such as scavenging of archaic proteins, signaling, and transmission of pathogens (20). In this study, we also show that an exosome-associated protein, Alix, is specifically enriched in amyloid plaques of AD brain sections, suggesting a novel role for exosomes in AD pathogenesis.