PLD2 MODULATES LIPID SIGNATURES AND NETWORK EXCITABILITY IN ALZHEIMER’S DISEASE

Alzheimer’s disease (AD) is the most common neurodegenerative dementia and is characterized by progressive cognitive decline accompanied by amyloid-beta (Aβ) plaque deposition and tau pathology. Beyond classical hallmarks, growing evidence highlights neuronal hyperexcitability and network dysfunction as early and clinically relevant features of AD. However, the molecular mechanisms linking amyloid pathology, tau signaling, and altered neuronal activity remain to be understood.
Lipids are essential regulators of synaptic structure, membrane dynamics, and excitability, and genetic as well as lipidomic studies implicate lipid dysregulation as a major risk factor for AD.
Phospholipase D2 (PLD2), a lipid-modulating enzyme that generates phosphatidic acid, has emerged as a potential mediator of amyloid-driven synaptic dysfunction. We investigated
the role of PLD2 in AD and Aβ–tau crosstalk using AD mouse models and cellular systems.
In the amyloidogenic J20 mouse model, PLD2 ablation improved memory performance and conferred protection against pharmacologically-induced seizures. Consistent with this phenotype, hippocampal lipidomic profiling identified specific lipids that correlate with seizure susceptibility, revealing lipid signatures associated with neuronal vulnerability in amyloid pathology. PLD2 deletion led to a marked reduction in hippocampal microglial coverage and altered morphology, while astrocytic distribution remained unchanged, indicating a selective impact on neuroinflammatory states. Analyses of tau pathology revealed unchanged total hippocampal tau levels following PLD2 deletion, prompting focused investigation into tau subcellular localization and tau–lipid interactions as downstream effectors of PLD2-dependent signaling. These findings position PLD2 as a key regulator linking amyloid pathology and neuronal excitability, supporting lipid-targeted strategies as a promising avenue for AD intervention.