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...
Note: Transcript has been edited for clarity and accuracy.Kevin Foskett: Kishore, why do you think there is no neurodegeneration in the Alzheimer's mouse brain despite chronic high Ca 2+ varicosities and blebs?Brian Bacskai and Kishore Kuchibhotla: Kevin, we have found that the moderate calcium overload can persist for quite some time, suggesting that even though the dendrite might not be functioning properly, it has not completely degenerated. In addition, we have no evidence that this leads to cell body loss in the neuronsa sort of dendritic pruning. Tom Fagan:We had one question submitted by email: "Does Ca 2+ not compete with heavy metals such as cadmium or lead, and if so, what would the consequence be in AD pathogenesis?" Anyone want to field that one? Ilya Bezprozvanny: Cadmium and lead have much higher affinity for calcium channels than calcium (1,000-fold), so Ca 2+ is not likely to compete them out.James Moyer: Kishore, are you able to visualize dendritic degeneration (e.g., in response to challenge) us-ing your in vivo approach? And does this susceptibility differ in transgenics?Brian Bacskai and Kishore Kuchibhotla: James, are you referring to dendritic degeneration in a nontransgenic mouse or in response to an acute lesion? James Moyer: Kishore, in response to glutamate challenge or some other acute insult.Brian Bacskai and Kishore Kuchibhotla: James, we can see dendrites respond rapidly to high glutamate concentrations but have not compared that carefully to transgenic mice.Beth Stutzmann: Kishore, I think you partially addressed my follow-up question to Kevin's, but have you looked further down into the cell body regions to determine extent of calcium overload? Brian Bacskai and Kishore Kuchibhotla: Beth, we have not fully characterized the cell bodies in layer 5 just yet.
Tom Fagan: I am Tom Fagan and I will be moderating today when necessary. Bruce Kagan is going to start us off with a brief introduction.Bruce Kagan: In 1993, Arispe et al. [1] reported that Aβ formed ion channels, and proposed that channels could cause cellular pathology and toxicity. Abundant evidence now supports this view, including the facts that virtually all amyloids form channels and that Aβ can inhibit long-term potentiation (LTP), depolarize neurons, allow cytochrome C efflux from mitochondria [2], and kill cells. Channel formation readily explains most amyloid pathophysiology, including memory disturbance, calcium dysfunction, membrane depolarizations, increased reactive oxygen species (ROS), sensitivity to toxins, and apoptosis.Larry Nault: Bruce, do these channels have a hypothetical geometry? A pipe or a duct? Bounded by what?Bruce Kagan: Larry, Arispe and Guy proposed several possible models for the pore. Recently, Arispe 1 Note: The transcript has been edited for clarity and accuracy. has published evidence [3] that specific regions of the peptide seem to line the pore.Tom Fagan: Bruce, how many channels does it take to kill a cell? Bruce Kagan: Tom, it depends on the size of the cell. The Aβ channels are large, electrically, and would create a significant leak. A single pore could reduce the sodium (Na+) concentration by about 10 micromolar per second.Tom Fagan: Bruce, how does that compare to normal leakage?Bruce Kagan: Tom, it again depends on the cell. For a neuron, which must maintain a tight membrane for signaling, a single pore would pose a significant but not lethal leak.Wonmuk Hwang: How specific are these channels? I understand that they have a distribution of sizes, which likely cause them to be nonspecific.Bruce Kagan: Won, the channels have been described as permeable to a variety of cations including sodium and calcium. There is little selectivity amongst cations.
Tom Fagan: I am Tom Fagan and I will be moderating our chat today. Chet, do you want to start us off with a topic? ChetMathis: Hank, where does SPECT amyloid imaging in humans stand? Hank F. Kung: We are doing I-123 IMPY now [IMPY, or 6-iodo-2-(4'-dimethylamino-)phenyl-imidazo[1,2a]pyridine, is a thioflavin derivative that has binding affinity for amyloid-β (Aβ) in solution and in postmortem Alzheimer disease (AD) samples] [1]. The data look good but we are not ready to publish yet. Bill, what is the status of your Pittsburgh compound B (PIB) study in AD patients? Bill Klunk: We have done about 30 subjects. 1 Note: The transcript has been edited for clarity and accuracy. Hank F. Kung: Mike Welch told me that Washington University has done 70 patients.Reisa Sperling: How about some discussion of the anatomic distribution of PIB retention and its relationship to hippocampal atrophy/dysfunction? Edward Zamrini: Bill, while amyloid pathology is most evident in the parietotemporal areas, PIB seems to concentrate in the frontal lobes more. Any new thoughts on that? Bill Klunk: Actually, the latest data show [PIB binding] to be highest in the precuneus, with parietal second and frontal a close third.
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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