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 tract, 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 criteria. According to the SYstematic Review Center for Laboratory Animal Experiment (SYRCLE) risk of bias tool, we reported 22 out of 29 studies with a high risk of bias. The present findings support the purported role of
trehalose in autophagic flux and protein refolding. This review identified several other lesser-known 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 adverse events and improvements in the outcome parameters 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.