Editor’s note: On 21-24 October 2008, the first Beijing Symposium on Aging and Neurodegeneration, aka BSAN, took place at Capital Medical University, Beijing. It was organized jointly by Xiao-liang Wang of the Institute Materia Medica at the Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing; Cynthia Lemere of Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts; and Xiao-min Wang of Beijing’s Capital Medical University. The Alzforum editors were there only in spirit; hence we are all the more pleased nonetheless to be able to offer our readers a rapid report of this conference. It comes to you courtesy of Carmela Abraham, Randall Bateman, Bruce Lamb, Cynthia Lemere, Malu Tansey, Kostas Vekrellis, Weiming Xia (see full IDs below), and Tsinghua University student Raymond Ko. These conference speakers and participants generously agreed to forego a well-deserved rest on the long trip back home from Beijing and instead pitched in and wrote summaries of the talks and selected posters for the world AD/PD research community. Our thanks go to Cindy Lemere for coordinating this volunteer effort and to all intrepid scientist-authors!—Gabrielle Strobel.

View conference photos.

BSAN Story
In an effort to bring together neuroscience researchers from the East and the West, the 2008 Beijing Symposium on Aging and Neurodegeneration (BSAN) was initiated in March 2008 when I (Cindy Lemere) visited my collaborator and friend, Xiao-liang Wang, in Beijing. Xiao-min Wang was invited to join us as organizers of this meeting and graciously provided the venue for our symposium. Together, Wang and Wang found support for the meeting through grants and local biotechnology companies. Ying Peng, Qiaoqiao Shi, Ling Wang, and Hui Zhang did an outstanding job arranging the meeting and website, for which we are all very grateful. Following registration and a small speaker's dinner on the first night, October 22 and 23 saw a series of 40-minute scientific presentations at Capital Medical University. In addition to the 18 invited speakers from China, Singapore, Greece, and the U.S., some 60 students, postdoctoral research fellows, and faculty attended. Students and postdocs presented about 20 posters. The meeting focused on pathophysiology, biology, pharmacology, and pathomechanisms of aging and neurodegeneration, as well as on therapies for age-related neurological diseases. Lively discussion followed each talk and was evident at the poster sessions, coffee breaks, lunches, and at the superb dinners hosted by Xiao-liang Wang (Peking duck) and Xiao-min Wang (Chinese Hot Pot). The meeting concluded with an impressive sightseeing trip to the Great Wall and Ming Tombs on 24 October, a delightful day with bright blue skies. Read on below for summaries of the talks, in order of presentation, as provided by the contributors listed above.

Carmela Abraham (Boston University School of Medicine): Klotho, Aging and Alzheimer's Disease
Abraham presented compelling data that the levels of the anti-aging gene Klotho and its protein product change as non-human primates and rodents age. Specifically, microarrays indicate that old monkeys have lower levels of Klotho (alpha) in white matter (WM) than do young monkeys. Furthermore, Klotho is downregulated in the brains of mouse models of Alzheimer disease. Analysis of microarray results obtained from oligodendrocyte cell lines treated with soluble Klotho, or untreated, may identify new pathways regulated by Klotho. In culture and in Klotho-overexpressing mice, upregulation of Klotho leads to IGF-1 signaling inhibition and an increase in antioxidant gene transcription. An exciting new finding cited by Abraham is that Klotho levels in normal breast tissue are high, but in breast cancer the levels are very low, suggesting that Klotho may be a tumor suppressor (Wolf et al., 2008). This prompted her to consult the Oncomine database, which revealed that Klotho is downregulated in a variety of brain cancers (glioblastoma multiforme, oligodendroglioma, and astrocytoma). Thus, activation of Klotho expression could be beneficial in normal aging, AD, and cancer (see ARF related news story).

Jiang-ping Jia (Xuanwu Hospital, Capital Medical University, Beijing): MCI and Dementia in China
While U.S.-ADNI has made significant progress during the past three years, Chinese neurologists have embarked on similar approaches and initiated multiple studies on its vast population of AD and MCI patients. Jianping Jia illustrated how basic and clinical research in neurodegenerative diseases can benefit from the large patient population that is being systematically analyzed for their clinical manifestation, neuropsychological evaluation, imaging, and eventual pathological examination. A gradual increase of the elderly population in China has been observed, jumping from 5 percent of population aged over 60 years old in 1990 to 11 percent in 2007. The prediction will be 17 percent in year 2025 and 31 percent in 2050, owing to a better standard of living and increased longevity. This translates into the same number as the entire U.S. population as being over 60 years old in China.

Urged on by the aging population and its associated financial burdens, the Chinese government has allocated more funding for research, e.g., a recent initiative of approximately $1 billion of funding for experimental drug discovery. Funded by the government 11th Five-Year Plan, Jia leads the Chinese Dementia and MCI Longitudinal Study, which involves a large number of hospitals and six major centers spanning across 22 provinces in China. The aims of his study are to assess the prevalence of dementia, MCI, and its major subtypes among elderly Chinese; examine the risk and protecting factors for dementia and MCI; monitor the progression of MCI (converting to AD versus maintaining cognitively normal conditions); and set up sensitive cognitive tests for MCI patients. The Prospective Longitudinal Cohort Study enrolls community-based subjects and hospital-based consecutive patients with MCI or dementia. Subjects will undergo cognitive evaluation, and MCI patients will subject to biological tests (e.g., routine blood tests), MRI, and genetic analysis. Follow-up examination will be performed on MCI, AD, and vascular dementia patients. The Cross-Sectional Study covers 320 hospitals with the participation of 5,400 doctors and 1,800 patients. The population-based survey will be carried out in three cities to obtain demographic data along with physical examination and systematic genetic tests. The magnitude of these studies can be further exemplified by Jia’s recent effort to analyze the variation of promoter regions of multiple genes related to amyloid-β protein metabolism. He has recruited approximate 1,000 sporadic AD patients, 1,000 age-matched controls, as well as all members of 50 familial AD families. The impact of promoter variants on transcription efficiency was examined and linked to the risk of AD. Jia’s presentation prompted an exciting discussion on possible incorporation of CSF collection and biomarker analyses of his thousands of subjects. (For more on this and other ADNI-like studies around the world, see ARF related news story.)

Yi-zheng Wang (Institute of Neuroscience, Shanghai Institute of Biological Sciences—SIBS, Chinese Academy of Sciences, Shanghai): TRPC Channels Promote Cerebellar Granular Neuron Survival
The transient receptor potential channels (TRPC) form hetero- and homo-trimers. For example, TRPC14 and 5, or TRPC3, 6, and 7, combine to form active, non-selective channels that allow the passage of calcium or sodium ions. TRPC3 and 6 are highly expressed in cerebellar granular neurons, especially during development, and these channels mediate BDNF-dependent protection against apoptosis induced by serum deprivation. BDNF activates TRPC3 and 6 and triggers intracellular calcium elevation, and phosphorylation of ERK and CREB, leading to neuronal survival (Zhou et al., 2008; Tai et al., 2008).

Jian-xing Song (National University of Singapore): Structural Mechanism and Molecular Design to Enhance Regeneration of the Injured CNS Axons by Targeting Nogo-NGR and Eph-Ephrin Interfaces
The failure of the CNS to regenerate results from the presence, in the adult myelin, of molecules that inhibit axon outgrowth. The two classes of inhibitors are 1) Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp) acting via the Nogo-66 receptor (NgR), and 2) ephrin working via the transmembrane tyrosine kinases Eph receptors. Thus, the interfaces between these ligands and receptors can be targets for drug design to treat CNS axonal injury. First, the three-dimensional structure of Nogo-66 needed to be determined, but the protein was insoluble in physiologic buffers. Song and colleagues then discovered that pure water is the best solvent for Nogo-66 and solved its 3D structure. The group then determined other structures of these inhibitors and their signaling pathways. Identification of these structures allowed for the discovery and design of small-molecule antagonists aimed at blocking the interface between the ligands and their receptors. These molecules could become new drugs that could facilitate regeneration in the injured CNS. (See also Li et al., 2008.)

Ying Peng (Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing): L-3-n-Butylphthalide Improves Cognitive Impairment in a Transgenic AD Mouse Model
DL-3-n-Butylphthalide (DL-NBP) is a synthetic multi-target compound based on an active fraction of an extract from Chinese celery seed (Apium graveolens). It is now being tested for neuroprotection in Phase 3 clinical trials for ischemia in China. L-NBP, a chiral isomer, has been shown to be even more neuroprotective in rodent models of ischemia and in an i.c.v. Aβ-infused rat model. For this reason Peng has tested it in triple-transgenic mice (3xTg-AD) that develop plaques and tau pathology with aging. Mice (10.7 months of age) were given 15 mg/kg L-NBP or vehicle by oral gavage five days a week for 4.5 months. L-NBP improved spatial learning and memory deficits in the day 7 probe trial of the Morris water maze. Aβ levels in brain homogenates were reduced. Total plaque burden was reduced while thioflavin S-labeled fibrillar plaques remained stable. L-NBP directed APP processing toward the non-amyloidogenic pathway by increasing cerebral levels of α-APPs, ADAM 10, ADAM 17, and PKC-α; however, APP levels were unchanged. L-NBP reduced gliosis and oxidative stress, but did not have a significant effect on phosphorylation of tau. In vitro, L-NBP increased α-APPs secretion and reduced Aβ levels in neuroblastoma SK-N-SH cells overexpressing wild-type human APP695, further suggesting that the drug shifts APP processing towards the non-amyloidogenic pathway. Further studies are underway in a three-way collaboration among the labs of Peng, Xiao-liang Wang, and Lemere (where Peng recently completed these studies as a postdoc prior to assuming a faculty position in Beijing; see also Peng et al., 2008).

Bruce Lamb (The Cleveland Clinic, Ohio): New Insights into Alzheimer’s Disease Using Transgenic Mouse Models
Lamb presented his laboratory’s recent data investigating the mechanisms underlying neuronal cell cycle activation observed in both human AD as well as transgenic mouse models of the disease. Similar to human AD, the genomic-based R1.40 transgenic mouse model of AD exhibits evidence of expression of cell cycle proteins and DNA replication in a subset of neurons vulnerable to degeneration in AD. These cell cycle events (CCEs) proceeded in a specific temporal and spatial pattern within the R1.40 transgenic mice. Lamb provided evidence that the induction of the neuronal CCEs was dependent upon the amyloidogenic processing of APP and initiated substantially prior to the onset of Aβ deposition in this model. This implies a role of soluble Aβ species in the formation of CCEs. In support of this idea, direct application of Aβ oligomers (but not monomers) to primary cortical neurons was capable of inducing increased BrdU incorporation. In a separate set of studies, Lamb presented data that neuronal CCEs also correlated with alterations in the activation of cortical microglia. In support of an active role of neuroinflammation in the induction of CCEs, LPS injections and NSAID administration were shown to promote or inhibit neuronal CCEs, respectively (see ARF related news story).

Biao Chen/Piu Chan (Xuanwu Hospital, Capital Medical University, Beijing): Age Associated Increase in Neuromelanin Leads to an Increased Expression of α-Synuclein and Neuronal Death in the Human Substantia Nigra
In an effort to examine age-related changes involved in nigrostriatal dopaminergic degeneration in Parkinson disease, Chen performed stereological counts of neurons in the substantia nigra from 19 normal individuals ranging from 17 to 84 years of age. The number of nigral neurons and nigral neurons with neuromelanin (NM) labeling decreased with aging, whereas NM-negative neuronal counts were only slightly reduced. Interestingly, α-synuclein (SYN) and NM showed an association in nigral neurons: SYN-positive/NM-negative neurons were decreased while SYN-positive/NM-positive neurons were increased with aging. Tyrosine hydroxylase (TH) expression was inversely correlated with α-synuclein. Thus, while the total number of nigral neurons decreases with aging, NM and α-synuclein appear to be increased and TH reduced the remaining dopaminergic neurons, possibly making them more vulnerable to cell death. In addition, Chen briefly stated his effort in the Chinese Biomarker Initiative and National Consortium on PD/AD involving 30-50 hospitals and ~3,000 patients, and his plan of a small trial of brain amyloid imaging. More results are expected in the near future.

Weiming Xia (Brigham &Women’s Hospital and Harvard Medical School, Boston): Exploring Oligomeric Amyloid as Alzheimer's Biomarker
Xia presented a recently published study (Xia et al., Arch Neurology, in press, 2008) on the analysis of oligomeric Aβ from AD patients’ plasma samples. The Xia lab established a sensitive method to measure oligomeric Aβ from different sources by ELISA. In collaboration with Dennis Selkoe from the same institution, the Xia lab has analyzed plasma samples from 36 AD and 10 control human subjects that were collected over the past eight years. Compared to monomeric Aβ species (full-length and N-terminal-truncated Aβ40/42), higher levels of oligomeric Aβ were found in plasma from AD patients. Longitudinal analysis of sequential plasma samples from the same subjects suggests that monomeric Aβ42 and oligomeric Aβ decrease over a one- to two-year period. Further studies of postmortem brain tissues from a separate set of 10 AD and seven control cases revealed much higher levels of monomeric Aβ42 and oligomeric Aβ in the brains of AD patients compared to control brains, suggesting that both forms decline over time in plasma and increase their insolubility in the brain. Because current amyloid imaging does not reveal the levels of oligomeric Aβ in human brains, biochemical analysis of plasma and CSF biomarkers becomes even more important (see ARF related news story).

Lin Li (Xuanwu Hospital, Capital Medical University, Beijing): Experimental Studies of Traditional Chinese Medicine to Treat Alzheimer's Disease
Li presented studies examining the effects of the Chinese herbal medicine Shen-wu (SW) on a wide variety of animal models of Alzheimer disease (AD), including APP transgenic mice as well as Aβ injection models. SW is a combination of six different traditional Chinese herbs that is currently under Phase 3 clinical trials for treating AD in China. Li presented data demonstrating that intragastric administration of SW was capable of a wide variety of effects in AD models. These include reductions in soluble Aβ levels and Aβ deposition in APP transgenic mice as well as improvements in memory performance as measured in the Morris water maze following a six-month administration of SW. In addition, SW treatment had a variety of other effects in other animal models, including reductions in tau phosphorylation, decreased oxidative stress, and reductions in microglial activation. Taken together, Dr Li’s studies suggest that SW administration is capable of affecting a variety of phenotypes related to AD pathogenesis and thus may prove efficacious as a multi-target drug in the treatment of AD. Future studies will be required to further identify the active components of SW and the molecular pathways through which SW acts on AD phenotypes (see also Wang et al., 2004; Zhong et al., 2007).

Cynthia Lemere (Brigham & Women's Hospital and Harvard Medical School): Active Amyloid-β Immunotherapy: Effects on Cognition and Plaque Burden in Aged Caribbean Vervets
Lemere presented the results of a preclinical Aβ immunotherapy trial in 22 non-human primates called Caribbean vervets, aged 18-24 years, funded by ELAN and Wyeth. Animals were randomized into three treatment groups base on age, gender, CSF Aβ40 levels, and cognition. All animals were trained in novel objection recognition (NOR). A subset of four vervets per group was trained in delayed-non-match-to-sample (DNMTS) testing using the Cambridge Neuropsychological Test Automated Battery, or CANTAB. Vervets were immunized seven times over 9.5 months with either aged Aβ1-42 plus adjuvant QS-21, or dAβ1-15 plus QS-21 (dAβ1-15 is a short Aβ immunogen targeting the B cell epitope and avoiding an Aβ T cell epitope, Seabrook et al., 2006), or vehicle (QS-21 alone). Two animals in the vehicle group died of natural causes early in the study. Anti-Aβ40 antibodies were detected by ELISA in all animals immunized with Aβ1-42 and in six of seven animals immunized with dAβ1-15, although in lower quantities. Plaque burden was reduced in the antibody responders, but CSF Aβ levels were unchanged due to high variability between the animals. Cognitive decline progressed in vehicle control animals but remained stable in the vervets immunized with Aβ1-42 (DNMTS) and improved in vervets immunized with dAβ1-15 (NOR and DNMTS) from pre- to post-vaccination. Microhemorrhage was not observed in any of the immunized animals. This study provides support for Aβ immunotherapy in early stages of AD.

Yuan Luo (Center for Integrative Medicine, University of Maryland School of Medicine, Baltimore): Stress Response Protects Against β Amyloid Toxicity In Vivo
Oligomeric Aβ has been shown to be toxic to cells. It blocks LTP and causes synaptic dysfunction and memory impairment. Heat shock proteins play a role in protecting organisms against toxicity by re-establishing cellular homeostasis. Luo's group previously showed that EGb761 (Gingkolide A, from gingko biloba extract) but not antioxidants (Congo red, vitamin E, and vitamin C) protected C. elegans worms overexpressing human Aβ42 from their paralysis phenotype (Cao et al., 2007). EGb761 increased resistance to oxidative stress, and treated worms lived longer. Next, the temperature was shifted from 16-23o C to induce a heat shock response in the worms. The investigators were surprised to find that transient heat shock resulted in a delay in paralysis that corresponded with increased expression of the small heat shock protein HSP16.2 and a reduction in oligomeric Aβ, although total Aβ levels were unchanged. There was some synergy between heat shock and EGb761 when applied together; however, heat shock was more effective than EGb761 alone. These results suggest that transient heat shock and EGb761 may share molecular mechanisms, including lowering of Aβ oligomerization, leading to protection against Aβ toxicity (see also Wu et al., 2008).

Randall Bateman (Washington University School of Medicine, St. Louis, Missouri): Human CNS Protein Kinetics: An Approach to the Study of Alzheimer Disease
Bateman reviewed biomarkers in Alzheimer disease and focused on CSF biomarkers including Aβ and tau. He presented evidence for dynamic changes in human CSF Aβ over hours and reviewed possible causes for these rapid changes, including changes in production by synaptic activity (Bateman et al., 2007). He then reviewed methodology to measure Aβ production and clearance rates in the human CNS and the results of these studies in younger normal controls (roughly 8 percent/hour production and clearance rates, Bateman et al., 2006). Results from a recent study of a γ-secretase inhibitor indicated that measuring production rates is a sensitive and robust method for direct assessment of production inhibitors. Bateman then discussed ongoing studies in participants with autosomal- dominant causative mutations of Alzheimer disease (see eFAD Research) and the cross-sectional and longitudinal studies measuring clinical onset and progression, neuro-psychometrics, structural, functional, and amyloid imaging and the formation of an international consortium, the Dominantly Inherited Alzheimer Network (DIAN; see upcoming Alzforum report).

Jian-Zhi Wang (Tongji Medical College, HUST, Wuhan): Tau Hyperphosphorylation in Cell Fate Decision
Wang presented data which suggested that cells overexpressing tau exhibit marked resistance to apoptosis induced by various apoptotic stimuli, including staurosporine, camptothecin, and hydrogen peroxide. In N2a cells, apoptotic stimuli induced activation of GSK3 and concurrent increases in tau hyperphosphorylation, suggesting that the anti-apoptotic effect of tau involves tau phosphorylation and GSK3. The resistance of neuronal cells bearing hyperphosphorylated tau to apoptosis was also evident by the presence of uncleaved caspase-3 and unfragmented nuclei. Wang suggested that cells with hyperphosphorylated tau escape apoptosis and enter a “degeneration” state. GSK3 overexpression did not strengthen apoptotic stimulus-induced cell apoptosis in the presence of high levels of tau. Further, she presented data demonstrating that tau phosphorylation was accompanied by reduction in β-catenin phosphorylation and in nuclear translocation of β-catenin. Overexpression of β-catenin in N2A cells also conferred resistance to apoptosis, likely because of a competitive phosphorylation between tau and β-catenin by GSK3 (see also Li et al., 2007).

Jau-Shyong Hong (Neuropharmacology Section of NIEHS/NIH, Research Triangle Park, North Carolina): Role of Inflammation in the Pathogenesis of Parkinson's Disease: Models, Mechanisms, and Therapeutic Interventions
Hong gave an overview of the importance of the role of inflammation as the “secret killer” in many modern-day diseases (cancer, neurodegeneration, heart disease). He listed the environmental factors associated with PD as including infectious agents: bacteria (LPS), viruses (HIV), and pesticides (rotenone, paraquat). He put forth the premise that glial cells are key players in disease and prime targets for therapy. Hong’s laboratory has focused on the use of morphinans as anti-inflammatory therapies, and he has been involved in clinical trials using dextromethorpan in China. He proposed that while microglia may overproduce inflammatory factors that can be neurotoxic, astrocytes are capable of producing a number of trophic factors that promote survival of neurons. After describing a number of inflammation models, his laboratory has developed to induce progressive and selective nigral dopaminergic neuron loss in rodents, Hong stressed that the self-propelling cycle of microgliosis is likely to be the main driver of neuronal toxicity. Therefore, his approach has been to identify agents that modulate microglia activity, including morphinans (naloxone, morphine, dextromethorphan), dynorphins, enkephalin, and the tripeptide GGF. In collaboration with Fulton Crews at the University of North Carolina, he proposes that pursuing a combinatorial approach (use of valproate, an HDAC inhibitor that induces BDNF and GDNF production) combined with anti-inflammatory therapy (using small molecules) may be an effective way to treat neurodegenerative diseases such as PD and perhaps others (see also Gao and Hong, 2008).

Kostas Vekrellis (Biomedical Research Foundation of the Academy of Athens, Greece): α-Synuclein Clearance: A Role for the Lysosome
Vekrellis presented data on primary cortical neurons, suggesting that the pathogenic α-synuclein mutation (A53T-mediated) toxicity following adenoviral infection is likely due to abnormal macroautophagy of α-synuclein. Specifically, he demonstrated that the rapamycin-induced punctae on EGFP-LC3-transduced neurons do not occur after knockdown of ATG5 with siRNA. Surprisingly, overexpression of WT α-synuclein had no effect on the activity of the ubiquitin proteasome system (UPS) in rat cortical primary cultures. The overall conclusions reached by his analyses are that chaperone-mediated autophagy (CMA) and macroautophagy are responsible for degradation of monomeric WT α-synuclein in neurons, and that expression of mutant (A53T) α-synuclein causes lysosomal dysfunction via CMA impairment and upregulation of macroautophagy. These data suggest that identifying molecules that can correct CMA impairment may reveal a novel therapeutic intervention for PD. In the future, Vekrellis and his colleague, Stephanis, plan to investigate if A53T expression in live animals also leads to lysosomal impairment in vivo (see also Vogiatzi et al., 2008).

Xiao-liang Wang (Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing): Role and Regulation of Potassium Channels in Neuronal Apoptosis in AD, PD Models
Neuronal excitability depends on potassium (K+) channels. In addition, K+ channel activation has been shown to induce neuronal apoptosis. The K+ channel blocker TEA reduces apoptosis and increases cell viability. In particular, the potassium channel Ik has been shown to open prior to apoptosis in Aβ-mediated neuronal cell death. Wang presented a series of in vitro and in vivo studies demonstrating the role of 10 different potassium channel subunits in AD and PD. Treating rat primary hippocampal neuronal cultures with Aβ25-35, and intracerebroventricular infusion with Aβ25-35, both resulted in increased mRNA expression and protein levels of the potassium channel subunits Kv2.1 and Kv4.2, and in neuronal damage. TEA blocked cell death and apoptosis in these models. A role for potassium channels in neurodegeneration was demonstrated in PD models, as well. A study conducted by Qiaoqiao Shi (a Ph.D. student in Wang's lab; presented as a poster at the meeting) showed that MPP+ treatment increased Ik density and MPTP treatment increased mRNA and protein levels of the K+ channel subunit, Kv3.1. Transfection of cells with A53T mutant α-synuclein resulted in increased sensitivity to MPP+ and MPTP treatment. TEA lowered apoptosis induced by these treatments. Wang also examined K+ channels in A53T transgenic mice at three, nine, and 15 months of age and found that with aging, animals showed behavioral deficits and upregulation in specific K+ channel subunits, especially in the striatum and substantia nigra. His work suggests that specific potassium channel subunits may be suitable drug targets for treating neurodegenerative diseases (see also Yu et al., 2006).

Malu Tansey (University of Texas Southwestern Medical Center, Dallas): Role and Regulation of TNF-Dependent Neuroinflammatory Mechanisms of Models of Parkinson's Disease
Tansey presented her lab's work on the use of dominant-negative inhibitors of tumor necrosis factor (DN-TNFs) in cell-based and animal models of PD, which demonstrates a critical role for soluble TNF in LPS- and 6-OHDA-induced nigral dopaminergic (DA) degeneration. In recent studies, the use of anti-TNF gene therapy (lentiviral DN-TNF) was shown to have comparable efficacy in attenuating nigral DA neuron loss and behavioral deficits, as does chronic infusion of the DN-TNF inhibitor. An important focus of the research is on identification of molecular regulators of microglial-derived TNF and of the sensitivity of nigral DA neurons to inflammatory insults. Tansey presented her group’s work on recent identification of RGS10 (Regulator of G-protein Signaling-10) as a microglial-enriched protein that may be an important regulator of the microglia stress response. RGS10 is itself downregulated in a proteasomal-dependent manner by chronic low-dose LPS or TNF stimulation. Deletion of RGS10 in microglia results in overproduction of TNF and other inflammatory mediators with enhanced toxicity on dopaminergic cells. Interestingly, deletion of RGS10 in DA neuron-like cells heightens their sensitivity to microglial-derived inflammatory mediators through an as yet unknown mechanism. Tansey reported that RGS10 knockout mice display increased microglial load and, when exposed to chronic systemic inflammation, they develop nigral DA neuron loss. Taken together, these data suggest that RGS10 may be protective against age-associated inflammation-related neurodegeneration (see also Lee et al., 2008). Efforts are under way to identify other protective factors against inflammation-induced degeneration. In a recent collaboration with Matthew Goldberg at UTSW, the group has identified parkin as another potential protective factor, as parkin-deficient mice display increased vulnerability to inflammation-related nigral degeneration when exposed to repeated systemic low-dose LPS injections (Frank-Cannon et al., 2008; ARF Live Discussion).

Overall Summary
The 2008 Symposium on Aging and Neurodegeneration brought together researchers from the worldwide AD and PD scientific community in China. This country is increasingly aware that its large and aging population will face a tremendous burden of neurodegenerative disease in coming decades, but it is also making increasing investments in its own research into these diseases. In an exciting new development, BSAN provided a platform for the exchange of ideas between some 75 Chinese and international scientists. It showcased many of the latest developments on studies in aging and neurodegeneration. Speakers presented pioneering research and invoked lively discussions with the audience. Presentations included exploration of the mechanisms underlying neurodegenerative diseases, such as inflammatory pathways, apoptotic pathways, heat shock proteins, and cell cycle events in AD and PD. Understanding these mechanisms may help identify biomarkers and therapeutic targets for neurodegenerative diseases. Several therapeutic strategies were presented, including the enhancement of an anti-aging protein, enhancement of a microglia stress response protein, Aβ immunotherapy, and discovery of Chinese herb constituents, all giving hope for effective clinical therapies in the future.—Cynthia Lemere, on behalf of the authors.


No Available Comments

Make a Comment

To make a comment you must login or register.


News Citations

  1. San Diego: Klotho Spins Threads Linking Aging and AD Research
  2. Presenilins—Grinding Gears in the Cell Cycle?
  3. Hot Plasma—Blood Aβ a Risk Marker for AD?

Webinar Citations

  1. Targeting Tumor Necrosis Factor—A Therapeutic Strategy for AD

Paper Citations

  1. . Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer. Oncogene. 2008 Nov 27;27(56):7094-105. PubMed.
  2. . Critical role of TRPC6 channels in the formation of excitatory synapses. Nat Neurosci. 2008 Jul;11(7):741-3. PubMed.
  3. . TRPC6 channels promote dendritic growth via the CaMKIV-CREB pathway. J Cell Sci. 2008 Jul 15;121(Pt 14):2301-7. PubMed.
  4. . Rational design, solution conformation and identification of functional residues of the soluble and structured Nogo-54, which mimics Nogo-66 in inhibiting the CNS neurite outgrowth. Biochem Biophys Res Commun. 2008 Sep 5;373(4):498-503. PubMed.
  5. . l-3-n-Butylphthalide ameliorates beta-amyloid-induced neuronal toxicity in cultured neuronal cells. Neurosci Lett. 2008 Mar 28;434(2):224-9. PubMed.
  6. . [Effect of shenwu capsule on the peripheral blood lymphocyte DNA of rat model induced by beta-amyloid injection]. Zhongguo Zhong Yao Za Zhi. 2004 Feb;29(2):176-9. PubMed.
  7. . [Clinical study on a randomized, double-blind control of Shenwu gelatin capsule in treatment of mild cognitive impairment]. Zhongguo Zhong Yao Za Zhi. 2007 Sep;32(17):1800-3. PubMed.
  8. . Dendrimeric Abeta1-15 is an effective immunogen in wildtype and APP-tg mice. Neurobiol Aging. 2007 Jun;28(6):813-23. PubMed.
  9. . Ginkgo biloba extract EGb 761 and Wisconsin Ginseng delay sarcopenia in Caenorhabditis elegans. J Gerontol A Biol Sci Med Sci. 2007 Dec;62(12):1337-45. PubMed.
  10. . Heat shock treatment reduces beta amyloid toxicity in vivo by diminishing oligomers. Neurobiol Aging. 2010 Jun;31(6):1055-8. PubMed.
  11. . Fluctuations of CSF amyloid-beta levels: implications for a diagnostic and therapeutic biomarker. Neurology. 2007 Feb 27;68(9):666-9. PubMed.
  12. . Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med. 2006 Jul;12(7):856-61. PubMed.
  13. . Phosphorylation of tau antagonizes apoptosis by stabilizing beta-catenin, a mechanism involved in Alzheimer's neurodegeneration. Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3591-6. PubMed.
  14. . Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression. Trends Immunol. 2008 Aug;29(8):357-65. PubMed.
  15. . Wild type alpha-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J Biol Chem. 2008 Aug 29;283(35):23542-56. PubMed.
  16. . Role of potassium channels in Abeta(1-40)-activated apoptotic pathway in cultured cortical neurons. J Neurosci Res. 2006 Nov 15;84(7):1475-84. PubMed.
  17. . Parkin deficiency increases vulnerability to inflammation-related nigral degeneration. J Neurosci. 2008 Oct 22;28(43):10825-34. PubMed.

Other Citations

  1. conference photos

External Citations

  1. website
  2. Oncomine
  3. DIAN

Further Reading