Transmissible Endosomal Intoxication: A Balance between Exosomes and Lysosomes at the Basis of Intercellular Amyloid...

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Endolysosomal system dysfunction is an early hallmark of Alzheimer's disease (AD).
• The endolysosomal pathway, including multivesicular bodies (MVBs) and lysosomes, is crucial for amyloid precursor protein (APP) processing and amyloid-beta (Aβ) peptide homeostasis.
• Dysregulation of this system contributes to the accumulation of toxic amyloid species.

Purpose of the Study:

• To review how endolysosomal system alterations in AD lead to the generation and impaired degradation of toxic amyloid species.
• To explore the link between MVB formation, APP processing, and Aβ generation.
• To introduce the concept of transmissible endosomal intoxication (TEI) in neurodegeneration.

Main Methods:

• Literature review focusing on endolysosomal function in Alzheimer's disease.
• Analysis of molecular mechanisms governing MVB formation and APP cleavage product sorting.
• Conceptual framework development for transmissible endosomal intoxication.

Main Results:

• MVB formation is intrinsically linked to amyloid species generation.
• Cellular machinery at MVBs dictates the fate of APP cleavage products (degradation vs. exosome release).
• AD-associated endolysosomal distortions promote exosome release and amyloid species propagation.

Conclusions:

• Altered endolysosomal function in AD shifts cellular processes towards amyloid species release via exosomes.
• The proposed transmissible endosomal intoxication (TEI) model explains self-perpetuating endosomal dysfunction and Aβ spread.
• TEI offers a novel perspective on the propagation of amyloid species in neurodegenerative diseases.