Intranasal administration of alpha-synuclein aggregates: a Parkinson's disease model with behavioral and neurochemical correlates

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder in which both alpha-synuclein (α-syn) and dopamine (DA) have a critical role. Our previous studies instigated a novel PD model based on nasal inoculation with α-syn aggregates which expressed parkinsonian-like behavioral and immunological features. The current study in mice substantiated the robustness of the amyloid nasal vector model by examining behavioral consequences with respect to DA-ergic neurochemical corollaries. In vitro generated α-syn oligomers and fibrils were characterized using atomic force microscopy and the thioflavin T binding assay. These toxic oligomers or fibrils administered alone (0.48 mg/kg) or their 50:50 combination (total dose of 0.48 mg/kg) were given intranasally for 14 days and "open-field" behavior was tested on days 0, 15 and 28 of the protocol. Behavioral deficits at the end of the 14-day dosing regime and on day 28 (i.e., 14 days after treatment completion) induced rigidity, hypokinesia and immobility. This was accompanied by elevated nigral but not striatal DA, DOPAC and HVA concentrations in response to dual administration of α-syn oligomers plus fibrils but not the oligomers by themselves. α-Syn fibrils intensified not only the hypokinesia and immobility 14 days post treatment, but also reduced vertical rearing and enhanced DA levels in the substantia nigra. Only nigral DA turnover (DOPAC/DA but not HVA/DA ratio) was augmented in response to fibril treatment but there were no changes in the striatum. Compilation of these novel behavioral and neurochemical findings substantiate the validity of the α-syn nasal vector model for investigating parkinsonian-like symptoms.

α‐Synuclein Oligomers: A Study in Diversity

“…αSn monomer concentration is important for its aggregation, where a higher concentration aggregates faster. This is also visible in the table, where αSn incubation is done, either at low concentrations for a longer period (up to 7 days), or at higher concentrations for a shorter time (<24 hrs) . The different conditions result in a heterogeneous group of αSOs.…”

“…According to the seeding and spreading mechanism hypothesis, (misfolded) αSn is secreted by cells and taken up by neighbouring cells, where it templates the misfolding of cellular monomeric αSn. There is evidence that large elongated αSOs, protofibrils, and sonicated fibrils, are able to function as seeds and spread the pathology ,,. Evidence that smaller spherical αSOs might be involved in spreading and seeding is currently scarce.…”

“…Despite the sparse evidence for αSO seeding ability, one study reported that αSOs, in contrast to fibrils, were able to spread pathology in vivo following injection in the olfactory bulb . In contrast, another group reported that αSOs were indeed able to spread pathology in vivo following injection in the brain, but fibril injection was more effective and also resulted in motor deficits, in contrast to αSOs ,…”

Intranasal delivery of dopamine to the striatum using glycol chitosan/sulfobutylether-β-cyclodextrin based nanoparticles

“…In fact, more recently many authors have investigated the effects of DA or L-Dopa intranasally applied [11][12][13][14][15][16][17]. Moreover, the intranasal administration has been used by different authors to test the prion-like spreading of pathological a-synuclein in the brain [18][19][20][21]. In particular, it has been reported that nasal administration of a-syn amyloidogenic species produce dopaminergic but also non-dopaminergic parkinsonian neurochemical alterations as well as behavioral deficits indicated by rigidity and reduced locomotor activity [18][19][20].…”

“…Moreover, the intranasal administration has been used by different authors to test the prion-like spreading of pathological a-synuclein in the brain [18][19][20][21]. In particular, it has been reported that nasal administration of a-syn amyloidogenic species produce dopaminergic but also non-dopaminergic parkinsonian neurochemical alterations as well as behavioral deficits indicated by rigidity and reduced locomotor activity [18][19][20]. In this respect, it has been demonstrated that there is a final common pathway linking olfactory neuroepithelial receptor cells with axonal projections of the olfactory bulb and these networks are connected to centrifugal neuronal afferents from the substantia nigra dopamine nuclei [22].…”