Endosomal dysfunction impacts extracellular vesicle release: Central role in Aβ pathology.

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Alzheimer's disease (AD) is a neurodegenerative disorder marked by cognitive decline and senile plaques.
• Amyloid precursor protein (APP) processing and amyloid-beta (Aβ) peptide aggregation are central to AD pathogenesis.
• Extracellular vesicles (EVs), including exosomes, are implicated in the intercellular transport of pathological molecules.

Purpose of the Study:

• To review the role of APP processing imbalance within EVs in Alzheimer's disease.
• To explore the involvement of autophagic, endosomal, and exosomal pathways in AD.
• To identify key molecular players and convergent mechanisms driving Aβ deposition and neurodegeneration.

Main Methods:

• Literature review focusing on APP processing, EVs, and related cellular pathways in AD.
• Analysis of studies investigating the interplay between endosomal-lysosomal-exosomal systems and APP metabolism.
• Identification of molecular components (Arc, p75, Rab11, retromer complex) associated with EV-mediated Aβ pathology.

Main Results:

• Imbalanced APP processing occurs within EVs, particularly exosomes, facilitating Aβ aggregation and plaque formation.
• Increased intraluminal vesicle (ILV) production and exosome release may represent a cellular response to endosomal dysfunction.
• This compensatory mechanism paradoxically enhances amyloidogenic APP processing and Aβ deposition.
• Dysfunctional endosomal-lysosomal-exosomal pathways contribute to elevated APP and Aβ levels in EVs.

Conclusions:

• EVs play a critical role in the propagation of AD pathology by sequestering and transporting APP processing machinery and Aβ.
• Key molecular players including Arc, p75, Rab11, and the retromer complex are implicated in this EV-mediated neurodegenerative process.
• Targeting these EV-related pathways presents a potential therapeutic strategy for Alzheimer's disease.