Extracellular vesicles: where the amyloid precursor protein carboxyl‐terminal fragments accumulate and amyloid‐β oligomerizes

Pérez‐González, Rocío; Kim, Yohan; Miller, Chelsea; Pacheco‐Quinto, Javier; Eckman, Elizabeth A.; Levy, Efrat

doi:10.1096/fj.202000823r

Cited by 37 publications

(39 citation statements)

References 79 publications

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“…However, detection of APP and its secretases in exosomes raise the possibility that extracellular vesicles, as reported in earlier studies (Perez-Gonzalez et al, 2020), may also serve as a potential site for de novo APP metabolism. Consistent with our results, Aβ 1-42 treatment which is known to increase cholesterol accumulation within cells (Mohamed et al, 2012) has been shown to decrease exosome secretion from astrocytes in a JNK-dependent pathway (Abdullah et al, 2016).…”

Section: Disease Models and Mechanisms • Dmm • Accepted Manuscriptmentioning

confidence: 72%

Implications of exosomes derived from cholesterol-accumulated astrocytes in Alzheimer's disease pathology

Cortez

Kamali-Jamil

et al. 2021

Disease Models &Amp; Mechanisms

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Amyloid β (Aβ) peptides generated from the amyloid precursor protein (APP) play a critical role in the development of Alzheimer's disease (AD) pathology. Aβ-containing neuronal exosomes, which represent a novel form of intercellular communication, have been shown to influence function/vulnerability of neurons in AD. Unlike neurons, the significance of exosomes derived from astrocytes remains unclear. In this study, we evaluated the significance of exosomes derived from U18666A-induced cholesterol-accumulated astrocytes in the development of AD pathology. Our results show that cholesterol accumulation decreases exosome secretion, whereas lowering cholesterol level increases exosome secretion from cultured astrocytes. Interestingly, exosomes secreted from U18666A-treated astrocytes contain higher levels of APP, APP-CTFs, soluble APP, APP secretases and Aβ1-40 than exosomes secreted from control astrocytes. Furthermore, we show that exosomes derived from U18666A-treated astrocytes can lead to neurodegeneration, which is attenuated by decreasing Aβ production or by neutralizing exosomal Aβ peptide with an Aβ antibody. These results, taken together, suggest that exosomes derived from cholesterol-accumulated astrocytes can play an important role in trafficking APP/Aβ peptides and influencing neuronal viability in the affected regions of the AD brain.

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Section: Disease Models and Mechanisms • Dmm • Accepted Manuscriptmentioning

confidence: 72%

Implications of exosomes derived from cholesterol-accumulated astrocytes in Alzheimer's disease pathology

Cortez

Kamali-Jamil

et al. 2021

Disease Models &Amp; Mechanisms

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“…Since the publication of the first protocol for isolation of BDEVs [ 76 ], the number of publications on this topic is increasing, with the first group of those publications reviewed in reference [ 98 ]. Since then, regarding neurodegenerative diseases such as AD, it has been shown that during the preclinical stage the expression of MHC class I markers in BDEVs is significantly upregulated [ 99 ] and that EVs isolated from murine brain are enriched with C-terminal fragments of APP (APP-CTFs), actively produced on the vesicles [ 76 , 100 ]. Furthermore, brain-derived EVs isolated both from early AD subjects and BCAS (bilateral common carotid stenosis) mice carry proteins involved in hypoxia such as EFEMP1, downstream activator of HIFs [ 101 ], highlighting the role of EVs in the hypoperfusion in human dementias.…”

Section: Future Perspectivesmentioning

confidence: 99%

Brain-Derived Extracellular Vesicles in Health and Disease: A Methodological Perspective

Brenna

Altmeppen

Magnus

et al. 2021

IJMS

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Extracellular vesicles (EVs) are double membrane structures released by presumably all cell types that transport and deliver lipids, proteins, and genetic material to near or distant recipient cells, thereby affecting their phenotype. The basic knowledge of their functions in healthy and diseased brain is still murky and many questions about their biology are unsolved. In neurological diseases, EVs are regarded as attractive biomarkers and as therapeutic tools due to their ability to cross the blood–brain barrier (BBB). EVs have been successfully isolated from conditioned media of primary brain cells and cerebrospinal fluid (CSF), but protocols allowing for the direct study of pathophysiological events mediated or influenced by EVs isolated from brain have only recently been published. This review aims to give a brief overview of the current knowledge of EVs’ functions in the central nervous system (CNS) and the current protocols to isolate brain-derived EVs (BDEVs) used in different publications. By comparing the proteomic analysis of some of these publications, we also assess the influence of the isolation method on the protein content of BDEVs.

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“…Upregulation of intraluminal vesicles (ILVs) in MVBs was reported in the Ts2Cje model of DS (D’Acunzo et al, 2019 ). It is noteworthy that exosomes contain APP-derived metabolites raising the possibility of a protective role in removing toxic products, including the C-terminal fragment of 99 amino acids (β-CTFs) and Aβ species (Perez-Gonzalez et al, 2020 ). If exosomes play this role, they may enhance Aβ clearance through a microglial cell-dependent pathway.…”

Section: Mechanisms Of Alzheimer’s Disease In Down Syndromementioning

confidence: 99%

Mechanistic Analysis of Age-Related Clinical Manifestations in Down Syndrome

Chen

Xing

Chen³

et al. 2021

Front. Aging Neurosci.

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Down syndrome (DS) is the most common genetic cause of Alzheimer’s disease (AD) due to trisomy for all or part of human chromosome 21 (Hsa21). It is also associated with other phenotypes including distinctive facial features, cardiac defects, growth delay, intellectual disability, immune system abnormalities, and hearing loss. All adults with DS demonstrate AD-like brain pathology, including amyloid plaques and neurofibrillary tangles, by age 40 and dementia typically by age 60. There is compelling evidence that increased APP gene dose is necessary for AD in DS, and the mechanism for this effect has begun to emerge, implicating the C-terminal APP fragment of 99 amino acid (β-CTF). The products of other triplicated genes on Hsa21 might act to modify the impact of APP triplication by altering the overall rate of biological aging. Another important age-related DS phenotype is hearing loss, and while its mechanism is unknown, we describe its characteristics here. Moreover, immune system abnormalities in DS, involving interferon pathway genes and aging, predispose to diverse infections and might modify the severity of COVID-19. All these considerations suggest human trisomy 21 impacts several diseases in an age-dependent manner. Thus, understanding the possible aging-related mechanisms associated with these clinical manifestations of DS will facilitate therapeutic interventions in mid-to-late adulthood, while at the same time shedding light on basic mechanisms of aging.

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Extracellular vesicles: where the amyloid precursor protein carboxyl‐terminal fragments accumulate and amyloid‐β oligomerizes

Cited by 37 publications

References 79 publications

Implications of exosomes derived from cholesterol-accumulated astrocytes in Alzheimer's disease pathology

Implications of exosomes derived from cholesterol-accumulated astrocytes in Alzheimer's disease pathology

Brain-Derived Extracellular Vesicles in Health and Disease: A Methodological Perspective

Mechanistic Analysis of Age-Related Clinical Manifestations in Down Syndrome

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