PINK1 and its familial Parkinson's disease-associated mutation regulate brain vascular endothelial inflammation.

Parkinson's disease (PD) is a debilitating disorder that affects movement. Inflammation-mediated endothelial dysfunction has been found to be involved in neurodegenerative diseases, including PD. More than 40 PTEN-induced putative kinase 1 (PINK1) mutations have been found in PD patients. The effects of PINK1 in vascular inflammation are as yet unknown. In this study, our findings revealed that PINK1 can be increased by the inflammatory cytokine tumor necrosis factor-α in primary human brain microvascular endothelial cells (HBMECs). We found that wild-type PINK1 prevents expression of the adhesion molecule vascular cell adhesion molecule-1 (VCAM-1), thus inhibiting the attachment of monocytes to brain endothelial cells. However, PINK1G309D, the loss-of-function mutation associated with early-onset familial PD, promotes expression of VCAM-1 and exacerbates attachment of monocytes to brain endothelial cells. Mechanism studies revealed that overexpression of wild-type PINK1 inhibits the VCAM-1 promoter by inhibiting the transcriptional activity of interferon regulatory factor 1 (IRF-1). However, PINK1G309D promotes the VCAM-1 promoter by increasing the transcriptional activity of IRF-1.

Changes of Cytokine Expression in the Hippocampus of Aβ1-42-Induced Alzheimer’s Disease Rat Model / 天津医药

Objective To explore changes of expression of pro-and anti-inflammatory cytokines in the hippocam-pus of Aβ1-42-induced Alzheimer’s disease (AD) rat model. Methods Twenty-four SD rats were divided into control group, PBS group (PBS was injected into CA1 area of hippocampus) and AD model group (Aβ1-42 was injected into CA1 area of hip-pocampus). The escape latency was evaluated by Morris water maze in three groups. Nissl staining was used to detect the le-sions of hippocampal CA1 neurons. Levels of amyloid precursor protein (APP) and protein phosphatase 2A (PP2A) in hippo-campus were measured by Western blot analysis. Real-time PCR was employed to examine the expressions of pro-inflamma-tory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), and the mRNA expressions of anti-inflammatory cytokines, including IL-4, IL-10 and transforming growth factor-β(TGF-β). Re-sults Rats subjected to Aβ1-42 injection in bilateral hippocampus led to a ability reduction of learning and memory, a loss of neurons in hippocampus and an increase in the expression of APP, and a decrease in PP2A expression in the hippocampus. In AD hippocampus, The mRNA expressions of the pro-inflammatory mediator, IL-1β, TNF-αand IFN-γ, were significant-ly up-regulated, but the expressions of the anti-inflammatory cytokines, IL-4, IL-10 and TGF-β, were markedly down-reg-ulated in AD group compared with those of control and PBS groups. Conclusion The pro-inflammatory/anti-inflammatory imbalance induced neuro-inflammation in AD rats, which was involved in pathogenesis of AD.