Blood-brain barrier dysfunction in aging induces hyperactivation of TGFß signaling and chronic yet reversible neural dysfunction.

Aging involves a decline in neural function that contributes to cognitive impairment and disease. However, the mechanisms underlying the transition from a young-and-healthy to aged-and-dysfunctional brain are not well understood. Here, we report breakdown of the vascular blood-brain barrier (BBB) in aging humans and rodents, which begins as early as middle age and progresses to the end of the life span. Gain-of-function and loss-of-function manipulations show that this BBB dysfunction triggers hyperactivation of transforming growth factor-ß (TGFß) signaling in astrocytes, which is necessary and sufficient to cause neural dysfunction and age-related pathology in rodents. Specifically, infusion of the serum protein albumin into the young rodent brain (mimicking BBB leakiness) induced astrocytic TGFß signaling and an aged brain phenotype including aberrant electrocorticographic activity, vulnerability to seizures, and cognitive impairment. Furthermore, conditional genetic knockdown of astrocytic TGFß receptors or pharmacological inhibition of TGFß signaling reversed these symptomatic outcomes in aged mice. Last, we found that this same signaling pathway is activated in aging human subjects with BBB dysfunction. Our study identifies dysfunction in the neurovascular unit as one of the earliest triggers of neurological aging and demonstrates that the aging brain may retain considerable latent capacity, which can be revitalized by therapeutic inhibition of TGFß signaling.

Paroxysmal slow cortical activity in Alzheimer's disease and epilepsy is associated with blood-brain barrier dysfunction.

A growing body of evidence shows that epileptic activity is frequent but often undiagnosed in patients with Alzheimer's disease (AD) and has major therapeutic implications. Here, we analyzed electroencephalogram (EEG) data from patients with AD and found an EEG signature of transient slowing of the cortical network that we termed paroxysmal slow wave events (PSWEs). The occurrence per minute of the PSWEs was correlated with level of cognitive impairment. Interictal (between seizures) PSWEs were also found in patients with epilepsy, localized to cortical regions displaying blood-brain barrier (BBB) dysfunction, and in three rodent models with BBB pathology: aged mice, young 5x familial AD model, and status epilepticus-induced epilepsy in young rats. To investigate the potential causative role of BBB dysfunction in network modifications underlying PSWEs, we infused the serum protein albumin directly into the cerebral ventricles of naïve young rats. Infusion of albumin, but not artificial cerebrospinal fluid control, resulted in high incidence of PSWEs. Our results identify PSWEs as an EEG manifestation of nonconvulsive seizures in patients with AD and suggest BBB pathology as an underlying mechanism and as a promising therapeutic target.

Glucocorticoids and the Brain: Neural Mechanisms Regulating the Stress Response.

In this chapter, we describe the central role of the brain in the glucocorticoid mediated stress response. We describe the mechanisms by which the brain gauges the severity of stress, mechanisms of hypothalamic-pituitary-adrenal axis (HPA) regulation, and how various sub-systems of the brain respond to glucocorticoid (GC) signaling to regulate stress behavior. In particular, we focus on the hippocampus, pre-frontal cortex, and amygdala, where GCs can induce a series of changes. Finally, we briefly discuss an apparent paradox in GC signaling: while exposure to glucocorticoids promotes the survival of an organism during acute stress, these same hormones in chronic excess can also cause damage and promote illness.

Stress and glucocorticoids promote oligodendrogenesis in the adult hippocampus.

Stress can exert long-lasting changes on the brain that contribute to vulnerability to mental illness, yet mechanisms underlying this long-term vulnerability are not well understood. We hypothesized that stress may alter the production of oligodendrocytes in the adult brain, providing a cellular and structural basis for stress-related disorders. We found that immobilization stress decreased neurogenesis and increased oligodendrogenesis in the dentate gyrus (DG) of the adult rat hippocampus and that injections of the rat glucocorticoid stress hormone corticosterone (cort) were sufficient to replicate this effect. The DG contains a unique population of multipotent neural stem cells (NSCs) that give rise to adult newborn neurons, but oligodendrogenic potential has not been demonstrated in vivo. We used a nestin-CreER/YFP transgenic mouse line for lineage tracing and found that cort induces oligodendrogenesis from nestin-expressing NSCs in vivo. Using hippocampal NSCs cultured in vitro, we further showed that exposure to cort induced a pro-oligodendrogenic transcriptional program and resulted in an increase in oligodendrogenesis and decrease in neurogenesis, which was prevented by genetic blockade of glucocorticoid receptor (GR). Together, these results suggest a novel model in which stress may alter hippocampal function by promoting oligodendrogenesis, thereby altering the cellular composition and white matter structure.

Elucidating the Complex Interactions between Stress and Epileptogenic Pathways.

Clinical and experimental data suggest that stress contributes to the pathology of epilepsy. We review mechanisms by which stress, primarily via stress hormones, may exacerbate epilepsy, focusing on the intersection between stress-induced pathways and the progression of pathological events that occur before, during, and after the onset of epileptogenesis. In addition to this temporal nuance, we discuss other complexities in stress-epilepsy interactions, including the role of blood-brain barrier dysfunction, neuron-glia interactions, and inflammatory/cytokine pathways that may be protective or damaging depending on context. We advocate the use of global analytical tools, such as microarray, in support of a shift away from a narrow focus on seizures and towards profiling the complex, early process of epileptogenesis, in which multiple pathways may interact to dictate the ultimate onset of chronic, recurring seizures.

The evolution of resistance genes in multi-protein plant resistance systems.

The genomic perspective aids in integrating the analysis of single resistance (R-) genes into a higher order model of complex plant resistance systems. The majority of R-genes encode a class of proteins with nucleotide binding (NB) and leucine-rich repeat (LRR) domains. Several R-proteins act in multi-protein R-complexes that mediate interaction with pathogen effectors to induce resistance signaling. The complexity of these systems seems to have resulted from multiple rounds of plant-pathogen co-evolution. R-gene evolution is thought to be facilitated by the formation of R-gene clusters, which permit sequence exchanges via recombinatorial mispairing and generate high haplotypic diversity. This pattern of evolution may also generate diversity at other loci that contribute to the R-complex. The rate of recombination at R-clusters is not necessarily homogeneous or consistent over evolutionary time: recent evidence suggests that recombination at R-clusters is increased following pathogen infection, suggesting a mechanism that induces temporary genome instability in response to extreme stress. DNA methylation and chromatin modifications may allow this instability to be conditionally regulated and targeted to specific genome regions. Knowledge of natural R-gene evolution may contribute to strategies for artificial evolution of novel resistance specificities.