Trehalose disaccharide has a stable neuroprotective effect used in inhibiting experimental neurodegeneration. However, the mechanism of its action on brain neurons remains largely unclear. In hepatocytes, the main target of trehalose is the activation of mTOR-independent autophagy, which is achieved by inhibiting the glucose transporter GLUT8, leading to energy deficiency. An increase in AMP levels activates AMP-dependent kinase AMPK by phosphorylation at Thr172 and further activates autophagy regulator kinase ULK1. In neurons, the GLUT8 transporter inhibitors and other disaccharides also activate autophagy, but less effectively than trehalose. The neuroprotective effect of trehalose includes a chaperone-like effect, inhibition of the accumulation of aberrant proteins, reduction of oxidative stress, increased antioxidant protection, and suppression of neuroinflammation. Similar to the effect on hepatocytes, trehalose triggers the activation of autophagy by the short signaling pathway pAMPK-pULK1. AMPK inhibition prevents the activation of autophagy in neurons and weakens the neurotherapeutic effect of trehalose. AMPK activation is accompanied by the pleiotropic effect of suppression of biosynthetic processes and cellular metabolism related to activation of mTOR-dependent autophagy; however, no such effect has been detected for trehalose. In vivo data on the relationship among GLUT8 expression, AMPK activity, and autophagy levels in the brain are analyzed. The therapeutic advantages of the molecular effects of trehalose in comparison with the activation of mTOR-dependent autophagy and the possibilities of their combined therapeutic use are discussed.