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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 a-synuclein (aSyn) in nigral dopaminergic neurons, it remains to be elucidated how cognitive decline arises. Here, we investigated the effects of distinct aSyn strains on cognition and the related neuropathology in the medial septum/diagonal band (MS/DB), a key region for cognitive processing. Bilateral injection of aSyn fibrils into the dorsal striatum potently impaired cognition in mice. The cognitive decline was accompanied by accumulation of phosphorylated aSyn 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 aSyn neurotoxicity in nigral dopaminergic neurons, we investigated whether FABP3 also participates in aSyn 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 aSyn, decrease in GABAergic neurons, and cognitive impairment caused by aSyn fibrils. Overall, the present study indicates that FABP3 mediates aSyn 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.
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https://hal-cea.archives-ouvertes.fr/cea-03116076
Contributor : Ronald Melki <>
Submitted on : Wednesday, January 20, 2021 - 9:30:38 AM
Last modification on : Friday, January 22, 2021 - 3:30:15 AM
Long-term archiving on: : Wednesday, April 21, 2021 - 6:12:58 PM

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Kazuya Matsuo, Yasushi Yabuki, Ronald Melki, Luc Bousset, Yuji Owada, et al.. Crucial Role of FABP3 in αSyn-Induced Reduction of Septal GABAergic Neurons and Cognitive Decline in Mice. International Journal of Molecular Sciences, MDPI, 2021, 22, pp.400. ⟨10.3390/ijms22010400⟩. ⟨cea-03116076⟩

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