A link between lipid-mediated signaling and inflammation during neurodegeneration

Abstract Neuroinflammation, oxidative stress, and mitochondrial dysfunction have been associated with the pathophysiology of Alzheimer’s disease (AD), either as a primary cause or as a secondary component of the pathogenic process. AD, the most common cause of dementia in the elderly, is characterized by the accumulation of intracellular tau neurofibrillary tangles and extracellular amyloid plaques. The main component of the plaque core is the amyloid β (Aβ)-peptide. Longitudinal studies have shown that the appearance of plaques and tangles, together with markers of inflammation, starts decades before the onset of clinical symptoms. Some components of the inflammatory response may promote resolution and facilitate Aβ clearance, while sustained inflammation induces neurotoxicity. Fatty acid-binding proteins (FABPs) have recently emerged as key regulators of cell metabolism and inflammation. They control the intracellular transport of lipids that function as both, ligands for transcription factors and substrates for enzymes involved in lipid metabolism. In AD and other pathological conditions, astrocytes upregulate FABP7 expression. This increase in FABP7 expression has been linked to mitochondrial dysfunction. Accordingly, FABP7 is especially abundant in astrocytes that are rich in cytoplasmic granules originated from degraded mitochondria. Our preliminary data indicate that FABP7 participates in the development of a pro-inflammatory phenotype in human astrocytes, while down-regulation of FABP7 reduces the expression of inflammatory markers. FABP7 regulates the inflammatory response at least through 2 different mechanisms that have been independently pursued as therapeutic targets in AD. These include the regulation of peroxisome proliferator-activated receptor (PPAR) signaling and the regulation of arachidonic acid metabolism by cyclooxygenase-2 (COX-2). This suggests that FABP7 could function as a key regulator of the inflammatory response in astrocytes and constitutes a potential therapeutic target in AD. By simultaneously regulating two central components of the inflammatory response, targeting FABP7 may confer enhanced therapeutic efficacy over conventional anti-inflammatory therapies. On the aforementioned context, we will determine the mechanism by which FABP7 regulates the inflammatory response in astrocytes (Aim 1) and we will determine the therapeutic potential of targeting FABP7 in AD mouse models (Aim 2). Lastly in Aim 3 we will evaluate the extent to which FABP7 expression correlates with biomarkers of AD pathology and the rate of cognitive decline in human subjects. This proposal will contribute to the understanding of the role of FABP7 in neurodegeneration and will provide in vivo proof of the value of modulating FABP7 expression as a therapeutic target in AD.