Soluble urokinase-type plasminogen activator receptor (suPAR) is elevated in caregivers of patients with parkinsonism.

Caregivers are integral to the care of those with neurological disorders such as Parkinson's Disease (PD), but are often burdened by stress, anxiety, and depression. Previous research has suggested that the foundation of such stress is low-grade systemic inflammation, as evidenced by increased interleukin 6 (IL-6) and C-reactive protein (CRP) levels. Soluble urokinase-type plasminogen activator receptor (suPAR) is a kidney disease risk factor and marker of chronic inflammation that integrates psycho-social stress and organ dysfunction. Caregivers of PD experience an extraordinary amount of stress and suPAR's role as prognostic marker has not yet been assessed in caregivers of PD. The aim of this study was to determine the relationship between suPAR levels and PD caregiver burden. Healthy volunteers who accompanied patients with parkinsonism (n = 35) donated blood samples, and complete blood counts (CBC), CRP, and suPAR levels were measured. Participants were then interviewed by telephone and stratified into primary and non-primary caregiver groups. Their caregiver burden was quantified through the Zarit Caregiver Burden Short Form (ZBI-12). The resultant data demonstrated higher plasma levels of suPAR and ZBI-12 scores for the primary caregiver group relative to the non-primary caregiver group (suPAR level: 3.73 vs. 2.72 ng/mL, p = 0.01; ZBI-12: 18.57 vs. 5.4, p < 0.0001; Table). The data also revealed a moderate positive correlation between suPAR and ZBI-12 scores. These findings not only demonstrate a correlation between elevated suPAR and caregiving burden in PD, but also further support and raise awareness for the overall psychosocial burden and stress experienced by those caregivers.

Epidermal growth factor treatment of female mice that express APOE4 at an age of advanced pathology mitigates behavioral and cerebrovascular dysfunction.

APOE4 is a major genetic risk factor for Alzheimer's disease and high amyloid-ß (Aß) levels in the brain are a pathological hallmark of the disease. However, the contribution of specific APOE-modulated Aß-dependent and Aß-independent functions to cognitive decline remain unclear. Increasing evidence supports a role of APOE in modulating cerebrovascular function, however whether ameliorating this dysfunction can improve behavioral function is still under debate. We have previously demonstrated that systemic epidermal growth factor (EGF) treatment, which is important for vascular function, at early stages of pathology (treatment from 6 to 8 months) is beneficial for recognition and spatial memory and cerebrovascular function in female mice that express APOE4. These data raise the important question of whether EGF can improve APOE4-associated cerebrovascular and behavioral dysfunction when treatment is initiated at an age of advanced pathology. Positive findings would support the development of therapies that target cerebrovascular dysfunction associated with APOE4 in aging and AD in individuals with advanced cognitive impairment. Therefore, in this study female mice that express APOE4 in the absence (E4FAD- mice) or presence (E4FAD+ mice) of Aß overproduction were treated from 8 to 10 months of age systemically with EGF. EGF treatment mitigated behavioral dysfunction in recognition memory and spatial learning and improved hippocampal neuronal function in both E4FAD+ and E4FAD- mice, suggesting that EGF treatment improves Aß-independent APOE4-associated deficits. The beneficial effects of EGF treatment on behavior occurred in tandem with improved markers of cerebrovascular function, including lower levels of fibrinogen, lower permeability when assessed by MRI and higher percent area coverage of laminin and CD31 in the hippocampus. These data suggest a mechanistic link among EGF signaling, cerebrovascular function and APOE4-associated behavioral deficits in mice with advanced AD-relevant pathology.

EGF Treatment Improves Motor Behavior and Cortical GABAergic Function in the R6/2 Mouse Model of Huntington's Disease.

Recent evidence indicates that disruption of epidermal growth factor (EGF) signaling by mutant huntingtin (polyQ-htt) may contribute to the onset of behavioral deficits observed in Huntington's disease (HD) through a variety of mechanisms, including cerebrovascular dysfunction. Yet, whether EGF signaling modulates the development of HD pathology and the associated behavioral impairments remain unclear. To gain insight on this issue, we used the R6/2 mouse model of HD to assess the impact of chronic EGF treatment on behavior, and cerebrovascular and cortical neuronal functions. We found that bi-weekly treatment with a low dose of EGF (300 µg/kg, i.p.) for 6 weeks was sufficient to effectively improve motor behavior in R6/2 mice and diminish mortality, compared to vehicle-treated littermates. These beneficial effects of EGF treatment were dissociated from changes in cerebrovascular leakiness, a result that was surprising given that EGF ameliorates this deficit in other neurodegenerative diseases. Rather, the beneficial effect of EGF on R6/2 mice behavior was concomitant with a marked amelioration of cortical GABAergic function. As GABAergic transmission in cortical circuits is disrupted in HD, these novel data suggest a potential mechanistic link between deficits in EGF signaling and GABAergic dysfunction in the progression of HD.