Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by loss of motor control due to a wide loss of dopaminergic neurons along the nigro-striatal pathway. Some of the mechanisms that contribute to this cell death are inflammation, oxidative stress, and misfolded alpha-synuclein-induced toxicity. Current treatments are effective at managing the early motor symptoms of the disease, but they become ineffective over time and lead to adverse effects. Previous research using intracerebral stem cell therapy for treatment of PD has provided promising results; however, this method is very invasive and is often associated with unacceptable side effects. In this study, we used an MPTP-injected mouse model of PD and intravenously administered neural precursors (NPs) obtained from mouse embryonic and mesenchymal stem cells. Clinical signs and neuropathology were assessed. Female mice treated with NPs had improved motor function and reduction in the neuroinflammatory response. In terms of safety, there were no tumorigenic formations or any detectable adverse effect after treatment. Our results suggest that peripheral administration of stem cell-derived NPs may be a promising and safe therapy for the recovery of impaired motor function and amelioration of brain pathology in PD.

Several common and debilitating neurodegenerative disorders are characterized by the intracellular accumulation of neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau protein. In Alzheimer’s disease (AD), NFTs are accompanied by extracellular amyloid-beta (Aβ), but primary tauopathy disorders are marked by the accumulation of tau protein alone, including forms of frontotemporal dementia (FTD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), among others. ¹⁸F-THK5351 has been reported to bind pathological tau as well as associated reactive astrogliosis. The goal of this study was to validate the ability of the PET tracer ¹⁸F-THK5351 to detect early changes in tau-related pathology and its relation to other pathological hallmarks. We demonstrated elevated in vivo ¹⁸F-THK5351 PET signaling over time in transgenic P301S tau mice from 8 months that had a positive correlation with histological and biochemical tau changes, as well as motor, memory, and learning impairment. This study indicates that ¹⁸F-THK5351 may help fill a critical need to develop PET imaging tracers that detect aberrant tau aggregation and related neuropathology in order to diagnose the onset of tauopathies, gain insights into their underlying pathophysiologies, and to have a reliable biomarker to follow during treatment trials.

Extensive experimental and human-derived evidence suggest that misfolded Aβ particles spread similarly to infectious prions. Moreover, peripheral administration of Aβ seeds accelerates brain amyloidosis in both susceptible experimental animals and humans. The mechanisms and elements governing the transport of misfolded Aβ from the periphery to the brain are not fully understood, although circulation and retrograde axonal transport have been proposed. Here, we demonstrate that injection of Aβ seeds in the tongue, a highly innervated organ, substantially accelerates the appearance of plaques in Tg2576 mice. In addition, the extra-nasal exposure of Aβ aggregates increased amyloid pathology in the olfactory bulb. Our results show that exposing highly innervated tissues to Aβ seeds accelerates AD-like pathological features, and suggest that Aβ seeds can be transported from peripheral compartments to the brain by retrograde axonal transport. Research in this direction may be relevant on different fronts, including disease mechanisms, diagnosis, and risk-evaluation of potential iatrogenic transmission of Aβ misfolding.

Frontotemporal dementia (FTD) encompasses a heterogenous and clinically diverse group of disorders, including the behavioural variant frontotemporal dementia, the non-fluent and the semantic variants of primary progressive aphasia. While these subtypes present with distinct clinical features, emerging evidence implicates neuroinflammation as a shared pathogenic mechanism. Nevertheless, little is known regarding the status of the peripheral immune system in the pathogenesis of FTD. Blood samples were obtained from 27 individuals with a clinical diagnosis of FTD (7 behavioural variants FTD, 10 non-fluent and 10 semantic variants of primary progressive aphasia) and 25 age-matched healthy controls. The immunophenotypes of peripheral immune cell populations were assessed with multicolour flow cytometry. Regulatory T cells were isolated and co-cultured with responder T cells and proliferation was determined by 3H-thymidine incorporation. The immune-related transcriptomic profile of isolated monocytes was analysed using the NanoString Human Inflammation Panel. Plasma levels of inflammatory cytokines and chemokines were quantified using the Olink® Target 48 Cytokine panel. Our analysis demonstrated that the suppressive function of regulatory T cells on responder T cells proliferation was significantly compromised in FTD individuals compared to healthy controls (P < 0.05). Transcriptomic profiling of FTD monocytes revealed a potential dysregulation of 153 immune-related genes. Enrichment analysis showed that these genes were mainly involved in chemokine-mediated signalling pathway, monocyte and lymphocyte chemotaxis, response to interferon-gamma and positive regulation of ERK1 and ERK2 cascades. Proteomic analysis of plasma inflammatory mediators showed a significant increase in the pro-inflammatory cytokine TNFa (P < 0.05) and the chemokines CXCL10, CCL3, CCL19, CSF1 (P < 0.05) and CXCL12 (P < 0.01) in FTD individuals compared to healthy controls. These findings provide the first evidence that the immunomodulatory function of regulatory T cells is compromised in individuals with FTD. In addition, there is a dysregulation of inflammation-related gene expression in peripheral monocytes and an increase of plasma inflammatory chemokines and cytokines in FTD individuals. Further investigation is warranted to assess the therapeutic potential of restoring dysfunctional regulatory T cells and modulating the inflammatory profile in the clinical setting of FTD.