CORTICAL CONNECTIONS GET CLOSER LOOK IN HEALTH, DISEASEThe idea of the default mode network, an interconnected set of brain regions that are active when the brain is resting and that power down during focused mental tasks, was first proposed in 2001, but it quickly became a hot topic in cognitive neuroscience and for Alzheimer's disease (AD) researchers. The seesaw activation and deactivation of the default network and task-related brain regions appears critical for peak performance on memory tasks and deactivation and network connectivity are disrupted early in AD, perhaps as a result of amyloid deposition [1].AD is not the only disease where network activity suffers. A new study in PNAS reveals that function of the default network, as measured by fMRI, is also altered in people with schizophrenia, and their healthy first-degree relatives [2]. The changes are somewhat different from those seen in AD -network connectivity is strengthened, for one, and overall network activity is increased both at rest and during task. The study, from Susan Whitfield-Gabrieli at MIT, suggests that changes in default mode activity and alterations in the normal balance between activation and deactivation contribute to the symptoms of schizophrenia, and could be part of the genetic risk for the disease.To look at the default network in people with schizophrenia, the researchers performed fMRI scans on subjects while they were idle, and then when they engaged in a simple memory test. That allowed assessment of the basal network activity, and the extent of deactivation that occurred during a task that required concentration. The study compared 13 volunteers with early phase schizophrenia, 13 unaffected first-degree relatives and 13 healthy controls. When subjects performed the test, suppression of the default mode network was most effective in controls, and decreased in both patients and relatives. Overall, the deactivation in the default network and activation of task-related areas were strongly correlated in control subjects, but the seesaw effect was much weaker in patients and relatives. The result was a consistent hyperactivity of the default network. In addition, the patients and relatives showed stronger connectively between the medial prefrontal cortex and the precuneous and the rest of the default network, whether measured at rest or during a task.The strength of connectivity and defect in deactivation correlated with poorer performance in the working memory task and stronger schizophrenia symptoms, suggesting that the default mode network could play an important role in the cognitive and clinical symptoms of schizophrenia. In addition, the observation that unaffected relatives show similar changes suggests that aberrant network activity stems from genetic risk and is causal, rather than just a consequence of the disease, Whitfield-Gabrieli told ARF. "In the future, it may be possible to use these fMRI measures as a way of diagnosing disease, or to figure out how patients are responding to treatment," she said.In terms of the...

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Knight Vision -SIRT1 Aids ADAM10, Slays Amyloid-β Unseasonably warm days gave way to some notable nights at this year's Keystone Symposium, Alzheimer's Disease Beyond Aβ, held 10-15 January at Copper Mountain, Colorado. One evening offering was a short talk from Gizem Donmez, a postdoctoral fellow in Leonard Guarente's laboratory at MIT. Donmez reported that SIRT1, the histone deacetylase linked to longevity, might protect against AD by boosting ADAM10 (aka α-secretase) and promoting nonamyloidogenic processing of amyloid-β protein precursor (AβPP). If true, then you might want to eat more carrots because the effect seems to rely on SIRT1 playing vassal to the retinoic acid receptor.SIRT1 is activated by caloric restriction, which protects against brain atrophy in primates. SIRT1 itself also protects against neurodegeneration in mouse models of AD [1], and previous work from Giulio Pasinetti's laboratory at Mount Sinai School of Medicine, New York, suggested that activation of α-secretase may be responsible [2]. Pasinetti and colleagues attributed the increase in α-secretase to SIRT1 inhibition of the Rho kinase ROCK1, previously linked to suppression of the non-amyloidogenic secretase). But Donmez's work suggests that there is more to the tale.To explore the relationship between SIRT1 and AD, Donmez and colleagues made mice with either the SIRT1 gene knocked out or overexpressed. For knockouts, Donmez used the cre/lox system driven by a nestin promoter, limiting SIRT1 loss to neurons. For overexpression, she knocked the SIRT1 gene into the β actin locus, getting a mild, twofold overexpression. Donmez tested the effects of the SIRT1 mice on Aβ pathology by crossing them with AβPP/PS1 transgenic animals (AβPPSwe/PS1∆E9). Donmez reported that the AβPP/PS1/SIRT1 knockouts die earlier than control AβPP/PS1 animals, and that the knockouts have increased amyloid plaques and gliosis. The increased pathology in these mice was accompanied by a reduction in α-secretase activity. In contrast, AβPP/PS1 mice overexpressing SIRT1 had reduced levels of Aβ 42 compared to controls and increased ADAM10 and ADAM10 mRNA. Levels of Notch intracellular domain, which is produced following α-secretase processing of the transmembrane receptor, were also increased when SIRT1 was overexpressed but not when it was knocked out. The results support the theory that SIRT1 can boost expression of the secretase.Donmez jousted with the ADAM10 promoter using chromatin immunoprecipitation assays to determine exactly how SIRT1 might exert its influence. She reported that the deacetylase attaches to the promoter very close to a binding site for the retinoic acid receptor (RAR)/retinoid X receptor (RXR) heterodimer. Activation of the ADAM10 gene depended on SIRT1 deacetylase activity (an inactive mutant has no effect) and also the presence of retinoic acid. The evidence suggests that SIRT1 deacetylates RAR leading to increased expression of ADAM10, presumably by allowing RAR to bind more tightly to the promoter. In support of this, Donmez found that R...

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