A Dichotomous Role for FABP7 in Sleep and Alzheimer’s Disease Pathogenesis: A Hypothesis

Abstract

Fatty acid binding proteins (FABPs) are a family of intracellular lipid chaperone proteins known to play critical roles in the regulation of fatty acid uptake and transport as well as gene expression. Brain-type fatty acid binding protein (FABP7) is enriched in astrocytes and has been implicated in sleep/wake regulation and neurodegenerative diseases; however, the precise mechanisms underlying the role of FABP7 in these biological processes remain unclear. FABP7 binds to both arachidonic acid (AA) and docosahexaenoic acid (DHA), resulting in discrete physiological responses. Here, we propose a dichotomous role for FABP7 in which ligand type determines the subcellular translocation of fatty acids, either promoting wakefulness aligned with Alzheimer’s pathogenesis or promoting sleep with concomitant activation of anti-inflammatory pathways and neuroprotection. We hypothesize that FABP7-mediated translocation of AA to the endoplasmic reticulum of astrocytes increases astrogliosis, impedes glutamatergic uptake, and enhances wakefulness and inflammatory pathways via COX-2 dependent generation of pro-inflammatory prostaglandins. Conversely, we propose that FABP7-mediated translocation of DHA to the nucleus stabilizes astrocyte-neuron lactate shuttle dynamics, preserves glutamatergic uptake, and promotes sleep by activating anti-inflammatory pathways through the peroxisome proliferator-activated receptor-γ transcriptional cascade. Importantly, this model generates several testable hypotheses applicable to other neurodegenerative diseases, including amyotrophic lateral sclerosis and Parkinson’s disease.

Relationship between sex, APOE genotype, endocannabinoids and cognitive change in older adults with metabolic syndrome during a 3-year Mediterranean diet intervention

“…APOE differences in the modulation of AEA and other NAEs (OEA, PEA, DHEA, DGLEA, LEA, POEA, and SEA) after MedDiet intervention may result from alterations in lipid signaling that have already been described among APOE -ε4 carriers [ 22 , 90 ]. Impairments in lipid transport machinery in the presence of the APOE4 isoform involve the neural receptor sortilin and the fatty acid binding protein 7 (FABP7), and have been shown to ultimately disrupt proper intracellular lipid handling and action [ 22 , 90 , 91 ].…”

The level of dementia biomarkers in type 2 diabetes mellitus

“…These findings are consistent with our studies. Additionally, there are studies demonstrating that APOE (Apolipoprotein E), which poses a high risk for the development of Alzheimer's disease, may alter the functional expression of FABP7 20 . The fact that APOE alleles and lipid metabolism disorders are involved in the common molecular pathology of Alzheimer's disease and diabetes suggests that FABP7 may also be involved in this pathway.…”

The Multifunctional Family of Mammalian Fatty Acid–Binding Proteins

“…In contrast, AA promoted FABP7-dependent cell migration via reduction in PPARγ and increased cyclooxygenase-2 levels ( 35 , 124 ). FA-specific roles for FABP7 have been proposed to mediate effects in Alzheimer’s disease, with AA binding stimulating inflammatory pathways and DHA imparting neuroprotection ( 129 ).…”