Crucial Role of FABP3 in αSyn-Induced Reduction of Septal GABAergic Neurons and Cognitive Decline in Mice

Abstract

In synucleinopathies, while motor symptoms are thought to be attributed to the accumulation of misfolded α-synuclein (αSyn) in nigral dopaminergic neurons, it remains to be elucidated how cognitive decline arises. Here, we investigated the effects of distinct αSyn strains on cognition and the related neuropathology in the medial septum/diagonal band (MS/DB), a key region for cognitive processing. Bilateral injection of αSyn fibrils into the dorsal striatum potently impaired cognition in mice. The cognitive decline was accompanied by accumulation of phosphorylated αSyn at Ser129 and reduction of gamma-aminobutyric acid (GABA)-ergic but not cholinergic neurons in the MS/DB. Since we have demonstrated that fatty acid-binding protein 3 (FABP3) is critical for αSyn neurotoxicity in nigral dopaminergic neurons, we investigated whether FABP3 also participates in αSyn pathology in the MS/DB and cognitive decline. FABP3 was highly expressed in GABAergic but rarely in cholinergic neurons in the MS/DB. Notably, Fabp3 deletion antagonized the accumulation of phosphorylated αSyn, decrease in GABAergic neurons, and cognitive impairment caused by αSyn fibrils. Overall, the present study indicates that FABP3 mediates αSyn neurotoxicity in septal GABAergic neurons and the resultant cognitive impairment, and that FABP3 in this subpopulation could be a therapeutic target for dementia in synucleinopathies.

Heart fatty acid-binding protein is associated with phosphorylated tau and longitudinal cognitive changes

“…Thus, we speculated that HFABP and tau pathology have synergistic effects on AD development. Third, HFABP may also regulate dopamine D2R (dopamine receptor 2) function in the striatum and anterior cingulate cortex and mediates αSyn neurotoxicity in septal GABAergic neurons to affect cognitive function and emotional behavior ( Yamamoto et al, 2018 ; Matsuo et al, 2021 ). Finally, recent studies suggested HFABP was associated with specific features of brain atrophy and white matter Hyperintensities burden, independently of amyloid and tau pathology biomarkers ( Clark et al, 2022 ; Vidal-Piñeiro et al, 2022 ).…”