Pericytes are perivascular mural cells of brain capillaries that are positioned centrally within the neurovascular unit between endothelial cells, astrocytes and neurons. This unique position allows them to play a major role in regulating key neurovascular functions of the brain. The role of pericytes in the regulation of cerebral blood flow (CBF) and neurovascular coupling remains, however, debatable. Using loss-of-function pericyte-deficient mice, here we show that pericyte degeneration diminishes global and individual capillary CBF responses to neuronal stimulus resulting in neurovascular uncoupling, reduced oxygen supply to brain and metabolic stress. We show that these neurovascular deficits lead over time to impaired neuronal excitability and neurodegenerative changes. Thus, pericyte degeneration as seen in neurological disorders such as Alzheimer’s disease may contribute to neurovascular dysfunction and neurodegeneration associated with human disease.

Summary A canonical feedforward circuit is proposed to underlie sensory cortical responses with balanced excitation and inhibition in layer 4 (L4). However, in another input layer, L6, sensory responses and the underlying synaptic circuits remain largely unclear. Here, cell-attached recordings in rat primary auditory cortex revealed that for the majority of L6 excitatory neurons, tonal stimuli did not drive spike responses, but suppressed spontaneous firings. Whole-cell recordings further revealed that the silencing resulted from tone-evoked strong inhibition arriving earlier than excitation. This pattern of inputs can be attributed to a parallel feedforward circuit with both excitatory and inhibitory inputs disynaptically relayed. In contrast, in the other neurons directly driven by thalamic input, stimuli evoked excitation preceding relatively weak inhibition, resulting in robust spike responses. Thus, the dichotomy of L6 response properties arises from two distinct patterns of excitatory-inhibitory interplay. The parallel circuit module generating preceding inhibition may provide a gating mechanism for conditional corticothalamic feedback.

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Activated protein C (APC) is a blood protease with anticoagulant activity and cell-signaling activities mediated by activation of protease-activated receptors 1 and 3 (PAR1, PAR3) via non-canonical cleavage1. Recombinant APC and/or its analogs with reduced (>90%) anticoagulant activity such as 3K3A-APC (Lys191–193Ala), engineered to reduce APC-associated bleeding risk while retaining normal cell signaling activity, have shown benefits in preclinical models of ischemic stroke2–6, brain trauma7, multiple sclerosis8, amyotrophic lateral sclerosis9, sepsis10,11, ischemic/reperfusion injury of heart12, kidney and liver13, pulmonary, kidney and gastrointestinal inflammation1,11, diabetes14 and lethal body radiation15. Based on proof of concept studies and an excellent safety profile in humans, 3K3A-APC has advanced to clinical trials as a neuroprotectant in ischemic stroke16,17. Recently, 3K3A-APC has been shown to stimulate neuronal production by human neural stem/progenitor cells (NSCs) in vitro18 via a PAR1-PAR3-sphingosine-1-phosphate receptor 1-Akt pathway19, suggesting the potential for APC-based treatment as a strategy for structural repair in the human central nervous system. Here, we report that late post-ischemic treatment of mice with 3K3A-APC stimulates neuronal production by transplanted human NSCs, promotes circuit restoration, and improves functional recovery. Thus, 3K3A-APC-potentiated neuronal recruitment from engrafted NSCs may offer a new approach to the treatment of stroke and related neurological disorders.

The overexpression of the colony-stimulating factor-1(CSF-1) by epithelial ovarian cancer cells enhances invasiveness and metastatic properties, contributing to the poor prognosis of the patients. It has been suggested that CSF-1 3Vuntranslated region containing AU-rich elements (ARE) could regulate CSF-1 posttranscriptional expression and be responsible for its aberrant abundance in such cancer cells. In this study, normal (NOSE.1) and malignant (Hey) ovarian epithelial cells were used to examine CSF-1 expression and regulation. CSF-1 overexpression in Hey cells was found to associate with increased invasiveness, motility, urokinase activity, and virulence of tumorigenicity, compared with NOSE.1 cells, which expressed little CSF-1. CSF-1 ARE was further found to serve as an mRNA decay element that correlates with downregulation of protein translation. Moreover, such downregulation was found more prominent in NOSE.1 than in Hey cells, suggesting differences in posttranscriptional regulation. As a variety of trans-acting factors [AU-binding protein (AUBP)] are known to modulate messenger stability through binding to such elements, we examined the protein content of both cell lines for their ability to bind the CSF-1 ARE. Our results strongly suggested the abundance of such AUBP activity in Hey cells. We isolated a 37-kDa AUBP, which was identified as glyceraldehyde-3-phosphate dehydrogenase (GAPDH). To summarize, our study identified GAPDH as an AUBP abundant in Hey cells, where it binds to CSF-1 ARE that imparts mRNA decay. These data suggest that GAPDH binding to CSF-1 ARE sequence prevents CSF-1 mRNA decay and subsequent down-regulation of CSF-1 protein translation, leading to CSF-1 overexpression and increased metastatic properties seen in ovarian cancer. (Cancer Res 2005; 65(9): 3762-71)