L‐Leucine Upregulates Lysosomal Biogenesis and Autophagy to Lower Plaques in 5XFAD Mouse Model of Alzheimer's Disease

ABSTRACT Twenty different amino acids are required for the human body for proper functioning as amino acids serve as building blocks for proteins. We screened different essential and non‐essential amino acids for the ability to stimulate lysosomal biogenesis and, interestingly, found an essential amino acid L‐leucine as the most potent one in stimulating lysosomal biogenesis in astrocytes. However, D‐leucine remained weaker than L‐leucine in terms of stimulation of lysosomal biogenesis. Accordingly, L‐leucine increased autophagy in cultured brain cells and in vivo in the brain of 5XFAD mice, one of the animal models of Alzheimer's disease (AD). L‐Leucine also stimulated the uptake and degradation of amyloid‐β in astrocytes and reduced the plaque load and improved cognitive functions in 5XFAD mice. Although L‐leucine was discovered about 200 years back, until now, no receptor has been identified for L‐leucine. Here, we noticed that L‐leucine binds to the ligand‐binding domain of peroxisome proliferator‐activated receptor α (PPARα) to activate this nuclear hormone receptor. Accordingly, L‐leucine remained ineffective in increasing lysosomal biogenesis and autophagy in PPARα −/− brain cells. Lentiviral establishment of full‐length PPARα , but not Y314D‐PPARα , reinstated the autophagy‐stimulating effect of L‐leucine in PPARα −/− astrocytes, emphasizing the importance of leucine's interaction with the Y314 residue. Moreover, oral L‐leucine decreased the plaque load and improved spatial learning and memory in 5XFAD mice, but not in 5XFAD ΔPPARα mice ( 5XFAD lacking PPARα ), highlighting the involvement of PPARα in the neuroprotective effects of L‐leucine. These results may be beneficial for AD patients. image