Neuronal fatty acid-binding protein enhances autophagy and suppresses amyloid-β pathology in a Drosophila model of Alzheimer's disease.

Fatty acid-binding proteins (FABPs) are small cytoplasmic proteins involved in intracellular lipid transport and bind free fatty acids, cholesterol, and retinoids. FABP3, the major neuronal FABP in the adult brain, is upregulated in the CSF of patients with Alzheimer's disease (AD). However, the precise role of neuronal FABPs in AD pathogenesis remains unclear. This study investigates the contribution of fabp, the Drosophila homolog of FABP3 and FABP7, to amyloid β (Aβ) pathology using a Drosophila model. Neuronal knockdown of fabp shortened the lifespan of flies and increased age-related protein aggregates in the brain. In an AD model, fabp knockdown in neurons increased Aβ accumulation and Aβ-induced neurodegeneration, whereas fabp overexpression ameliorated Aβ pathology. Notably, fabp overexpression stimulated autophagy, which was inhibited by the knockdown of Eip75B, the Drosophila homolog of the peroxisome proliferator-activated receptor (PPAR). The PPAR activator rosiglitazone restored autophagy impaired by fabp knockdown and reduced fabp knockdown-induced increased Aβ aggregation and cell death. Furthermore, knockdown of either fabp or Eip75B in the wing imaginal disc or adult fly brain reduced the expression of Atg6 and Atg8a. Additionally, treatment of the fabp knockdown AD model flies with polyunsaturated fatty acids, such as docosahexaenoic acid or linoleic acid, partially alleviated cell death in the developing eye, restored impaired autophagy flux, reduced Aβ aggregation, and attenuated Aβ-induced cell death. Our results suggest that Drosophila fabp plays an important role in maintaining protein homeostasis during aging and protects neurons from Aβ-induced cell death by enhancing autophagy through the PPAR pathway. These findings highlight the potential importance of neuronal FABP function in AD pathogenesis. Author summary: Alzheimer's disease (AD) is a neurodegenerative disease characterized by a gradual progression to severe cognitive impairment and dementia. Despite its high heritability, only a limited number of genes associated with AD have been identified. Understanding the role of disease-associated genes is critical to unraveling the pathology of AD. Given the abnormal protein aggregation seen in AD, genes that affect the degradation of aggregated proteins are expected to be important players. In this study, we focused on FABP, a lipid transport protein that has been observed at elevated levels in the cerebrospinal fluid of patients with AD. The specific role of this protein in neurons affected by AD remained elusive. Using a Drosophila model of AD, we found that reduced expression of fabp in neurons increased accumulation of amyloid β (Aβ) and exacerbated Aβ-induced neurodegeneration. Conversely, overexpression of fabp attenuated these phenotypes. Our results confirm that the protective effect of fabp is mediated through autophagy. In particular, we identified the involvement of the nuclear receptor PPAR in this process. We also demonstrated that neuronal fabp plays a critical role in protein aggregation and lifespan during aging. In conclusion, our study highlights the critical role of neuronal FABP as a regulator in AD pathology and aging. These findings contribute to a better understanding of the molecular mechanisms underlying AD and open avenues for potential therapeutic interventions. [ABSTRACT FROM AUTHOR]