Chronic nicotine improves cognitive and social impairment in mice overexpressing wild type α-synuclein

Abstract

In addition to dopaminergic and motor deficits, patients with Parkinson's disease (PD) suffer from non-motor symptoms, including early cognitive and social impairment, that do not respond well to dopaminergic therapy. Cholinergic deficits may contribute to these problems, but cholinesterase inhibitors have limited efficacy. Mice over-expressing α-synuclein, a protein critically associated with PD, show deficits in cognitive and social interaction tests, as well as a decrease in cortical acetylcholine. We have evaluated the effects of chronic administration of nicotine in mice over-expressing wild type human α-synuclein under the Thy1-promoter (Thy1-aSyn mice). Nicotine was administered subcutaneously by osmotic minipump for 6 months from 2 to 8 months of age at 0.4 mg/kg/h and 2.0 mg/kg/h. The higher dose was toxic in the Thy1-aSyn mice, but the low dose was well tolerated and both doses ameliorated cognitive impairment in Y-maze performance after 5 months of treatment. In a separate cohort of Thy1-aSyn mice, nicotine was administered at the lower dose for one month beginning at 5 months of age. This treatment partially eliminated the cognitive deficit in novel object recognition and social impairment. In contrast, chronic nicotine did not improve motor deficits after 2, 4 or 6 months of treatment, nor modified α-synuclein aggregation, tyrosine hydroxylase immunostaining, synaptic and dendritic markers, or microglial activation in Thy1-aSyn mice. These results suggest that cognitive and social impairment in synucleinopathies like PD may result from deficits in cholinergic neurotransmission and may benefit from chronic administration of nicotinic agonists.

Spiny Projection Neuron Dynamics in Toxin and Transgenic Models of Parkinson’s Disease

“…Levodopa or D1 agonism, but not D2 agonism rescues the deficits in novel object recognition and hippocampal LTP (Bonito-Oliva et al, 2014b ; Loiodice et al, 2018 ) suggesting that early dysfunction not only occurs in dSPN circuits but are manifesting in D1-dependent systems that extend beyond the striatum. Similar cognitive deficits have also been observed in alpha-synuclein overexpression (Subramaniam et al, 2018 ). MitoPark mice have progressive degeneration of DA neurons (Ekstrand et al, 2007 ) with motor impairment beginning at 12 weeks of age (Galter et al, 2010 ).…”

Activation of α7-nAChRs Promotes the Clearance of α-Synuclein and Protects Against Apoptotic Cell Death Induced by Exogenous α-Synuclein Fibrils

“…Recently, Federica Bono et al ( 2019 ) showed that nicotine activated the dopamine D3R-nAChR complex and prevented αSyn accumulation in primary cultures of mouse dopaminergic neurons and human iPSC-derived dopaminergic neurons. However, chronic nicotine administration showed no effect on the levels of αSyn in the SNpc and striatum of Thy1-αSyn mice (Subramaniam et al, 2018 ). Besides, nicotine has intracellular machinery that governs protein folding, transport and turnover via regulating endoplasmic reticulum and mitochondrial health (Srinivasan et al, 2014 ).…”

Gamma synuclein is a novel nicotine responsive protein in oral cancer malignancy

“…SNCG expression is normally restricted to the brain and peripheral neuronal tissues [ 14 ], and its aberrant expression in tissues other than those of the neuronal system is highly associated with human malignancy. Previous studies have reported that nicotine acting on brain nAChRs may affect SNCA aggregation, resulting in neuroprotection [ 15 – 17 ]. Recently, we reported that SNCG is abnormally expressed in OSCC and that its expression is strongly correlated with disease progression [ 2 ].…”