PLD3 affects axonal spheroids and network defects in Alzheimer's disease

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• The exact causes of cognitive decline in Alzheimer's disease (AD) remain unclear.
• Amyloid plaques are a hallmark of AD, but their precise role in neural dysfunction is debated.
• Axonal abnormalities are observed in AD, but their direct contribution to network dysfunction is not fully understood.

Purpose of the Study:

• To identify key mechanisms contributing to neural network dysfunction in Alzheimer's disease.
• To investigate the role of amyloid-plaque-associated axonal spheroids in disrupting neural connectivity.
• To explore the potential of targeting endolysosomal pathways for therapeutic intervention in AD.

Main Methods:

• Intravital calcium and voltage imaging in a mouse model of Alzheimer's disease.
• Analysis of axonal spheroid size, composition, and association with endolysosomal vesicles.
• Genetic manipulation of Pld3 expression in neurons to assess its impact on spheroid formation and function.

Main Results:

• Alzheimer's disease model mice exhibit significant disruption in long-range axonal connectivity.
• Enlarging axonal spheroids cause action-potential conduction blockades in a size-dependent manner.
• Pld3 gene, encoding a lysosomal protein, is linked to endolysosomal vesicle accumulation and spheroid growth, worsening axonal dysfunction.

Conclusions:

• Amyloid-plaque-associated axonal spheroids are major contributors to neural network dysfunction in Alzheimer's disease.
• Pld3-mediated endolysosomal biogenesis drives spheroid enlargement and axonal conduction blockades.
• Modulating endolysosomal biogenesis offers a potential therapeutic strategy for Alzheimer's disease, independent of amyloid removal.