Trehalose-releasing nanogels reduce α-synuclein-induced Lewy body-like inclusions in primary mouse hippocampal neurons

Parkinson's disease (PD) is the second most prevalent age-related neurodegenerative disorder, clinically characterized by both motor and non-motor symptoms. A key hallmark of PD is the accumulation of misfolded α-synuclein, which aggregates to Lewy bodies (LB) formed inside neurons. Trehalose, a disaccharide that induces autophagy, has been demonstrated to reduce α-synuclein aggregation <i>in vivo</i>. However, the enzyme trehalase rapidly degrades free trehalose, and its hydrophilicity causes poor penetration through the cell membrane. Thus, advanced trehalose delivery strategies are urgently needed. Herein, we investigated the effects of trehalose-bearing nanogels for reducing α-synuclein protein-induced perinuclear LB-like pathology in primary mouse hippocampal neurons. The study compares the effects of trehalose-releasing nanogel (TR) and trehalose-non releasing nanogel (TNR). The results showed that TR, but not TNR, nor free trehalose reduced LB-like inclusions in primary hippocampal neurons. The neuroprotective effects of TR may result from the synergistic effects of direct limitation of α-synuclein aggregates formation and trehalose release-induced autophagy promoting aggregates clearance. Overall, enhancing trehalose delivery with nanogels that can sustainably release trehalose could be worth further investigation as a new potential option for reducing α-synuclein aggregation in neurons affected by neurodegenerative diseases.