Exploring the PLD1-tau interaction in Frontotemporal Dementia.

Area of Science:

• Neuroscience
• Biochemistry

Background:

• Frontotemporal dementia (FTD) is a leading cause of young-onset dementia, characterized by cognitive decline and frontotemporal atrophy.
• Tauopathy is present in nearly 40% of FTD cases, but the molecular mechanisms driving tau aggregation and synaptic dysfunction are not fully understood.

Purpose of the Study:

• To investigate the role of Phospholipase D1 (PLD1) in FTD-associated tau pathology and synaptic deficits.
• To explore PLD1's contribution to synaptic dysfunction in FTD, considering its implication in Alzheimer's disease and amyotrophic lateral sclerosis.

Main Methods:

• Analysis of postmortem temporal and frontal cortices from FTD patients and controls.
• Utilized fluorescence-assisted single synaptosome long-term potentiation (FASS-LTP), immunofluorescence, proximity ligation assays (PLA), and PLD1-interactome proteomics.
• Examined PLD1 expression, co-localization with tau species and synaptic markers, and proteomic alterations in different cellular compartments.

Main Results:

• FTD brains showed reduced glutamatergic potentiation and elevated PLD1 expression in specific cortical regions.
• PLD1 co-localized significantly with pathological tau species (total, hyperphosphorylated, and acetylated tau oligomers) and synaptic markers.
• Proteomic analysis revealed compartment-specific alterations, including impaired synaptic proteostasis and increased astroglial involvement, with protein redistribution from synapses to cytosol.

Conclusions:

• PLD1 is a critical mediator of synaptic dysfunction and tau pathology in FTD.
• PLD1 acts through astroglial activation and disrupts synaptic proteostasis, contributing to neurodegeneration.
• PLD1 attenuation presents a potential therapeutic target for FTD and related tauopathies to restore synaptic integrity.