Intranasal administration of trehalose reduces α-synuclein oligomers and accelerates α-synuclein aggregation

Abnormal alpha-synuclein (alpha Syn), including an oligomeric form of alpha Syn, accumulates and causes neuronal dysfunction in the brains of patients with multiple system atrophy. Neuroprotective drugs that target abnormal alpha Syn aggregation have not been developed for the treatment of multiple system atrophy. In addition, treating diseases at an early stage is crucial to halting the progress of neuronal damage in neurodegeneration. In this study, using early-stage multiple system atrophy mouse model and in vitro kinetic analysis, we investigated how intranasal and oral administration of trehalose can improve multiple system atrophy pathology and clinical symptoms. The multiple system atrophy model showed memory impairment at least four weeks after alpha Syn induction. Behavioural and physiological analyses showed that intranasal and oral administration of trehalose reversed memory impairments to near-normal levels. Notably, trehalose treatment reduced the amount of toxic alpha Syn and increased the aggregated form of alpha Syn in the multiple system atrophy model brain. In vitro kinetic analysis confirmed that trehalose accelerated the aggregate formation of alpha Syn. Based on our findings, we propose a novel strategy whereby accelerated alpha Syn aggregate formation leads to reduced exposure to toxic alpha Syn oligomers, particularly during the early phase of disease progression. Tanaka et al. report that the intranasal administration of trehalose reduced toxic alpha-synuclein oligomers and increased alpha-synuclein aggregates in the hippocampus of a mouse model of human alpha-synuclein-inducible multiple system atrophy. This treatment may reduce exposure to toxic alpha-synuclein oligomers by accelerating the formation of aggregates and improve memory. Graphical Abstract