Trehalose,a unique nonreducing crystalline disaccharide,is a potential disease-modifying treatment for neurodegenerative diseases associated with protein misfolding and aggregation due to aging,intrinsic mutations,or autophagy dysregulation.This systematic review summarizes the effects of trehalose on its underlying mechanisms in animal models of selected neurodegenerative disorders（tau pathology,synucleinopathy,polyglutamine tra ct,and motor neuron diseases）.All animal studies on neurodegenerative diseases treated with trehalose published in Medline（accessed via EBSCOhost）and Scopus were considered.Of the 2259 studies screened,29 met the eligibility crite ria.According to the SYstematic Review Center for Laboratory Animal Expe riment（SYRCLE） risk of bias tool,we repo rted 22 out of 29 studies with a high risk of bias.The present findings suppo rt the purported role of trehalose in autophagic flux and protein refolding.This review identified several other lesserknown pathways,including modifying amyloid precursor protein processing,inhibition of reactive gliosis,the integrity of the blood-brain barrier,activation of growth factors,upregulation of the downstream antioxidant signaling pathway,and protection against mitochondrial defects.The absence of adve rse events and improvements in the outcome paramete rs were observed in some studies,which supports the transition to human clinical trials.It is possible to conclude that trehalose exerts its neuroprotective effects through both direct and indirect pathways.However,heterogeneous methodologies and outcome measures across the studies rendered it impossible to derive a definitive conclusion.Translational studies on trehalose would need to clarify three important questions:1)bioavailability with oral administration,2) optimal time window to confer neuroprotective benefits,and 3) optimal dosage to confer neuroprotection.