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

Kazuya Matsuo,Ronald Melki,Luc Bousset,Yuji Owada,Kohji Fukunaga,Yasushi Yabuki

doi:10.3390/ijms22010400

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.

Highlights

Synucleinopathies, including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), are neuropathologically characterized by Lewy bodies (LBs) and Lewy neurites (LNs), which contain α-synuclein in abundance [1]
(2) fatty acid-binding protein 3 (FABP3) is highly expressed in GABAergic neurons in the medial septum/diagonal band (MS/DB). (3) Fabp3 deletion suppresses phosphorylated αSyn (pαSyn) accumulation, reduction in GABAergic neurons, and resultant cognitive impairments
FABP3 may partly contribute to cognitive impairments due to septal GABAergic lesions in synucleinopathies

Summary

Introduction

Synucleinopathies, including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), are neuropathologically characterized by Lewy bodies (LBs) and Lewy neurites (LNs), which contain α-synuclein (αSyn) in abundance [1]. The most prominent symptom is Parkinsonism caused by deposits of misfolded αSyn and denervation in nigrostriatal dopaminergic neurons [2]. Another severe symptom is dementia, which has been documented to occur in more than half of PD patients in longitudinal prospective cohort studies over a decade [3,4]. While DLB is distinguished from PD by the onset of dementia prior to or within 1 year after that of Parkinsonism [7], αSyn pathologies in these cortical and limbic regions are observed at a relatively later in Braak stages [8]. While cortical and hippocampal αSyn pathologies are crucial for cognitive decline, there is likely to be involvement of other regions with the αSyn burden in cognitive symptoms at earlier stages

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