Alzheimer’s disease β-amyloid peptides are released in association with exosomes
Open accessAbstract
Although the exact etiology of Alzheimer's disease (AD) is a topic of debate, the consensus is that the accumulation of β-amyloid (Aβ) peptides in the senile plaques is one of the hallmarks of the progression of the disease. The Aβ peptide is formed by the amyloidogenic cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. The endocytic system has been implicated in the cleavages leading to the formation of Aβ. However, the identity of the intracellular compartment where the amyloidogenic secretases cleave and the mechanism by which the intracellularly generated Aβ is released into the extracellular milieu are not clear. Here, we show that β-cleavage occurs in early endosomes followed by routing of Aβ to multivesicular bodies (MVBs) in HeLa and N2a cells. Subsequently, a minute fraction of Aβ 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.
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Coordinated defects in ciliary signaling and intracellular trafficking may collectively facilitate extracellular vesicle and tunneling nanotube-dependent propagation of neurotoxic proteins across neural networks, potentially reinforcing progressive circuit dysfunction.
“These coordinated defects in ciliary signaling and intracellular trafficking may collectively facilitate the EV and TNT-dependent propagation of neurotoxic proteins across neural networks, thereby potentially reinforcing progressive circuit dysfunction (Figure 3A) [98,100,101,105].”
From The Impact of Neurotoxin Proteins Trafficked by Primary Cilia and Extracellular Vesicles in Neurodegenerative Diseases (2025) · cites this paper as [98]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredAmyloid-beta and tau propagate to other neurons via tunneling nanotubes and exosomes.
“Ultimately, Aβ and tau propagate to other neurons via TNT and exosomes [98,99,100,101].”
From The Impact of Neurotoxin Proteins Trafficked by Primary Cilia and Extracellular Vesicles in Neurodegenerative Diseases (2025) · cites this paper as [98]
The Discussion reports that a minute fraction of Aβ is released with exosomes and suggests that Aβ could use exosomes for intercellular transfer. It does not establish propagation to other neurons, and the passages do not address tau or tunneling nanotubes. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThese pathway alterations enhance extracellular vesicle-mediated export of pathogenic proteins including amyloid-beta and tau, facilitating their propagation between cells.
“These pathway alterations enhance the EV-mediated export of pathogenic proteins, including Aβ and tau, facilitating their propagation between cells [98,99].”
From The Impact of Neurotoxin Proteins Trafficked by Primary Cilia and Extracellular Vesicles in Neurodegenerative Diseases (2025) · cites this paper as [98]
The Discussion (page not provided) reports that a minute fraction of Aβ is secreted in association with exosomes and proposes that exosomes could mediate its transfer between cells. It does not report EV-mediated tau export or establish that the pathway alterations described in the citing sentence enhance export and propagation. (LLM, conf=0.89)
Experimental — accuracy not yet measuredExosomes isolated from the brain, CSF, and plasma of AD patients and/or AD animal models contain pathologic Aβ and tau.
“Exosomes isolated from the brain, cerebrospinal fluid (CSF), and plasma of AD patients and/or AD animal models contain pathologic Aβ and tau [73, 75–77].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [76]
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“Importantly, the content of EV cargo and membranes allows to differentiate and identify organ specificity, including brain-specific EV (Chivet et al., 2012; Rajendran et al., 2006).”
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“These pathway alterations enhance the EV-mediated export of pathogenic proteins, including A β and tau, facilitating their propagation between cells [98,99].”
- Authors
- Rajendran, L., Honsho, M., Zahn, T. R., Keller, P., Geiger, K. D., Verkade, P., & Simons, K.
- Affiliations
- Max Planck Institute of Molecular Cell Biology and Genetics (DE)
- Meso Scale Discovery (United States) (US)
- Technische Universität Dresden (DE)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-07-25
- Volume
- 103
- Issue
- 30
- Pages
- 11172-11177
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1544060
- OpenAlex
- W2156281143
- Cited by
- 1,343
- References
- 54
- Citations by year
- 2026: 59 · 2025: 50 · 2024: 85 · 2023: 80 · 2022: 98 · 2021: 114 · 2020: 115 · 2019: 116 · 2018: 83 · 2017: 86 · 2016: 90 · 2015: 67 · 2014: 48 · 2013: 58 · 2012: 61
- FWCI
- 12.81
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Explore Bristol Research (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Keywords
- Alzheimer's disease, amyloid-beta, exosomes, multivesicular bodies, early endosomes, amyloid precursor protein, beta-secretase, gamma-secretase, amyloid plaques, exosomal proteins, endosomal trafficking
- MeSH terms
- Adenoviridae, Alzheimer Disease, Animals, Brain, Cell Membrane, Cell Nucleus, Endocytosis, Exoribonucleases, HeLa Cells, Humans, Models, Biological, Peptides, Amyloid beta-Peptides, Mice
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