IGF2 prevents dopaminergic neuronal loss and decreases intracellular alpha-synuclein accumulation in Parkinson's disease models.

Parkinson's disease (PD) is the second most common late-onset neurodegenerative disease and the predominant cause of movement problems. PD is characterized by motor control impairment by extensive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). This selective dopaminergic neuronal loss is in part triggered by intracellular protein inclusions called Lewy bodies, which are composed mainly of misfolded alpha-synuclein (α-syn) protein. We previously reported insulin-like growth factor 2 (IGF2) as a key protein downregulated in PD patients. Here we demonstrated that IGF2 treatment or IGF2 overexpression reduced the α-syn aggregates and their toxicity by IGF2 receptor (IGF2R) activation in cellular PD models. Also, we observed IGF2 and its interaction with IGF2R enhance the α-syn secretion. To determine the possible IGF2 neuroprotective effect in vivo we used a gene therapy approach in an idiopathic PD model based on α-syn preformed fibrils intracerebral injection. IGF2 gene therapy revealed a significantly preventing of motor impairment in idiopathic PD model. Moreover, IGF2 expression prevents dopaminergic neuronal loss in the SN together with a decrease in α-syn accumulation (phospho-α-syn levels) in the striatum and SN brain region. Furthermore, the IGF2 neuroprotective effect was associated with the prevention of synaptic spines loss in dopaminergic neurons in vivo. The possible mechanism of IGF2 in cell survival effect could be associated with the decrease of the intracellular accumulation of α-syn and the improvement of dopaminergic synaptic function. Our results identify to IGF2 as a relevant factor for the prevention of α-syn toxicity in both in vitro and preclinical PD models.

Liver Dysfunction as a Novel Player in Alzheimer's Progression: Looking Outside the Brain.

Alzheimer's disease (AD) afflicts an estimated 20 million people worldwide and is the fourth-leading cause of death in the developed world. The most common cause of dementia in older individuals, AD is characterized by neuropathologies including synaptic and neuronal degeneration, amyloid plaques, and neurofibrillary tangles (NTFs). Amyloid plaques are primarily composed of amyloid-beta peptide (Aß), which accumulates in the brains of patients with AD. Further, small aggregates termed Aß oligomers are implicated in the synaptic loss and neuronal degeneration underlying early cognitive impairments. Whether Aß accumulates in part because of dysregulated clearance from the brain remains unclear. The flow of substances (e.g., nutrients, drugs, toxins) in and out of the brain is mediated by the blood-brain-barrier (BBB). The BBB exhibits impairment in AD patients and animal models. The effect of BBB impairment on Aß, and whether BBB function is affected by non-neurological pathologies that impair peripheral clearance requires further investigation. In particular, impaired peripheral clearance is a feature of nonalcoholic fatty liver disease (NAFLD), a spectrum of liver disorders characterized by accumulation of fat in the liver accompanied by varying degrees of inflammation and hepatocyte injury. NAFLD has reached epidemic proportions, with an estimated prevalence between 20% and 30% of the general population. This chronic condition may influence AD pathogenesis. This review article summarizes the current state of the literature linking NAFLD and AD, highlighting the role of the major Aß efflux and clearance protein, the LRP-1 receptor, which is abundantly expressed in liver, brain, and vasculature.

Diagnostic concordance of reporting lymphovascular invasion in breast cancer.

AIMS: This study aims to assess the diagnostic agreement of lymphovascular invasion (LVI) in invasive breast cancer (BC). METHODS: Data on LVI were collected from the UK National Health Service Breast Screening Programme pathology external quality assurance scheme database. 101 BCs assessed over a 10-year period (2004-2014) were included. Cases were scored by an average of 600 pathologists. Three H&E stained slides from each case were reviewed by three pathologists and additional variables were evaluated. RESULTS: In the whole series, the overall κ value was 0.4 (range 0.26-0.53). On review, LVI was detected in all three slides in 20 cases (20%), in two slides in 12 cases and in one of the three slides in 9 cases and was not seen in 60 cases. For concordance analysis, the first and last groups were used to represent cases with definite (LVI+) and absent LVI (LVI-), respectively. In the LVI+group (n=20), the level of agreement ranged from 0.54 to 0.99 (median 0.86). In the LVI- group (n=60), the level of agreement ranged from 0.52 to 1.00 (median 0.93), with 44% of cases showing interobserver concordance of >95%. There was a correlation between increasing number of involved lymphovascular spaces in the section and higher LVI reporting concordance. Some degree of retraction/fixation artefacts was observed in 35% of cases; this was associated with a lower concordance rate. CONCLUSIONS: The concordance of reporting LVI is variable. Cases without LVI and those with multiple involved vessels are likely to have the highest concordance and the highest detection rates.