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

초록

BackgroundThe pathology of Lewy body dementia (LBD) features neuronal alpha-synuclein (alpha-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.MethodsThe therapeutic efficacy and mechanisms of ULIUS were evaluated in primary cultured astrocytes and neuron-glia cocultures treated with alpha-syn preformed fibrils (PFFs), as well as in an LBD model induced by hippocampal alpha-syn PFF injection into neuronal alpha-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.ResultsRepeated 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 alpha-syn-induced elevation of TRPA1, toll-like receptors-2 (TLR2), interleukin-1 beta, and tumor necrosis factor-alpha 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 alpha-syn PFF-treated astrocytes.ConclusionsOur findings provide mechanistic insights into the reciprocal TRPA1-TLR2 signaling pathway in alpha-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.

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