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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