Ultrasonic repression of TRPA1-dependent astrocyte reactivity confers neuroprotection in models of Lewy body dementia

Background: The pathology of Lewy body dementia (LBD) features neuronal α-synuclein (α-syn) accumulation and astrocytic hyperactivation in cognitive brain circuits. Ultra-low-intensity ultrasound (ULIUS) modulates astrocyte function via transient receptor potential ankyrin 1 (TRPA1) and has been investigated for therapeutic applications in neurodegenerative diseases. Methods: The therapeutic efficacy and mechanisms of ULIUS were evaluated in primary cultured astrocytes and neuron-glia cocultures treated with α-syn preformed fibrils (PFFs), as well as in an LBD model induced by hippocampal α-syn PFF injection into neuronal α-syn-A53T transgenic mice. Astrocytic TRPA1 was modulated under pathologic conditions with ULIUS or a pharmacologic TRPA1 antagonist to determine calcium responses and transcriptional regulation of Trpa1 and inflammation-related genes. Neuropathological analyses for Lewy-like inclusions, neurodegeneration, and inflammation were performed in LBD mouse brains, with or without ULIUS. Spatial learning and memory were assessed using the Barnes maze. Results: Repeated transcranial ULIUS application was safe in long-term use and, unlike prolonged stronger ultrasound, did not cause hippocampal inflammation or neurodegeneration. It also prevented neuroinflammation and Lewy-like pathologies, rescuing cognitive impairment in LBD mice. ULIUS abolished α-syn-induced elevation of TRPA1, toll-like receptors-2 (TLR2), interleukin-1β, and tumor necrosis factor-α in LBD mouse brains. Mechanistically, both ULIUS and TRPA1 inhibitor blocked the sustained TRPA1-dependent calcium increase and the expression of inflammation-associated transcripts in α-syn PFF-treated astrocytes. Conclusions: Our findings provide mechanistic insights into the reciprocal TRPA1-TLR2 signaling pathway in α-syn-induced astrocyte pathology and underscore the disease-modifying potential of focused transcranial ULIUSm on astrocytes for the treatment of LBD. This study establishes a novel therapeutic strategy to alleviate neuroinflammation and cognitive decline associated with LBD. The demonstration of its long-term safety further supports ULIUS as a promising therapeutic strategy.