To a bird’s eyes, the San Diego convention center for the past 5 days would have looked like a mile-long human beehive. A swarm of 32,000 scientists and exhibitors exchanged information on 16,000 presentations, making the main belly of the building hum as discussions resonated across some 60 double rows of posters. The neurodegeneration buzz? Stay tuned as your Alzforum team distills it into news stories over the next few weeks.
Overall, the 37th annual conference of the Society for Neuroscience, held 3-7 November, showed convergence in some areas of AD research and divergence in others. One trend was a preponderance of presentations on oligomeric forms of the Aβ peptide. Labs are beginning to compare side-by-side the different forms described over the past few years. One group described their isolation of human oligomers from AD brain that were reportedly able to poison synapses, giving a boost to the disease relevance of these protein aggregates. There was a sense of consolidation around the notion that Aβ oligomers likely play a significant role in the cognitive deficits of people with AD, as a growing number of laboratories independently reported data from a variety of angles that were consistent with the central idea. At the human genetics level, there was even a report of a mutation in APP that causes a form of Aβ which rapidly forms oligomers but never forms fibrils at all, yet its carriers reportedly had clinical AD.
More broadly, Aβ and increasingly also tau research this year attempted to drill down into the synaptic biology of AD, picking up with an intense focus the historic observation that synaptic dysfunction, followed by synaptic loss, correlates better with cognitive symptoms than do plaques. The intraneuronal signaling pathways implicated are varied and bewilderingly complex, but Erk, GSK3, Wnt, Akt, Fyn, and calcineurin are a familiar presence in those studies.
By contrast, the emerging field of APP trafficking is at an even younger stage. Scientists agree that the retromer complex doing the trafficking is of central importance in AD, making AD at heart a disease of cell biology. But beyond that the field is presently generating a host of data that diverge in their details as research groups use different cell types and methodology. This field is still wide open and will likely converge again around several major pathways once more is known and labs have established methods to explore the process in the most directly disease-relevant model systems. Progress is also being made, albeit slowly, in figuring out the normal physiological function of APP, something that has so far proven elusive.
The technical wall that for some years had bloodied the noses of drug developers racing to make BACE inhibitors appears to have come down. Compounds that reliably lower levels of Aβ in spinal fluid are being presented, and several pharmaceutical companies are said to be refining their candidates and moving toward human tests. The relationship between Aβ toxicity and elevated BACE activity has also come in for closer scrutiny, and researchers are beginning to dissect the nature of BACE trafficking, stabilization, and transcriptional regulation.
Intriguingly, the tau and even α-synuclein fields are showing signs of following Aβ’s act in the sense that they, too, may prove to be more toxic in their early states of aggregation than in their classic pathological incarnation as tangles and Lewy bodies, respectively. Incidentally, if anyone thinks that tau tangles are unique to humans, they may want to know that a report of a chimp with abundant tangles did away with this dogma.
γ-secretase continued to surprise with a complex range of effects. New observations include a proposed role in mediating the benefits of enriched environments, and a role in controlling calcium streams out of the endoplasmic reticulum at the base of dendritic spines where the synapses sit. Presenilin FAD mutations appear to preclude these benefits and unleash calcium torrents that blunt excitability, respectively.
A growing number of presentations tried to nail down molecular mechanisms for the established overlap among risk for insulin-resistant diabetes mellitus, elevated cholesterol, and risk for dementia. The deplorably small trickle of studies on the biggest genetic risk factor for AD, i.e., ApoE, appeared to be picking up a bit with reports on ApoE’s novel effects on neprilysin- and IDE-mediated aggregation, as well as research of ApoE’s lipidation state, the role of other lipoprotein receptors in amyloidogenic APP processing, and the potential promise of LXR receptors. A number of laboratories are attempting to build integrative models of molecular processes of aging, and the anti-aging gene klotho entered the AD scene. Mitochondrial deficits show up in different guises across a wide range of studies.
A parallel trend in the offing is that many labs are trying to study AD models at ever-earlier stages, well before pathology settles in the brain. This is part of an effort not only to understand oligomers, but as importantly to get a handle on the defense mechanisms that synapses, neurons, and networks are mounting for some time before the disease process overwhelms these attempts to keep the system in balance.
The number of presentations on experimental treatments reported to have effects in mouse models is growing rapidly. Candidates that got attention this year include caffeine, available drugs to lower blood pressure, and the fish oil DHA. Combined with studies on research drugs not fit for human consumption, these data lead to the common frustration that if you are a mouse, scientists know of a host of ways of curing your "AD,” yet none of them have quite translated to humans yet. A more optimistic take might be that never before have drug companies and public drug-testing consortia had such a great number of compounds for AD tests in the clinic. The bottleneck lies not in targets or drug candidates, but rather in ways to diagnose AD earlier, and in biomarker-driven designs that make trials shorter, better, cheaper, and allow more drugs to be tested than is possible now.
Research continues apace on other neurodegenerative diseases that are of interest to AD researchers. We learned of problems and progress in relating pathology to different presentations of primary progressive aphasia, of advances in understanding the function and dysfunction of glia and how they may be exploited to treat spinal cord injury and motor neuron disease, and of the role of kinases in Parkinson disease.
On a lighter note, the AD Social proved to be the rowdiest affair of all socials hosted this past Tuesday night. No offense to the rest of neuroscience, but the Synapse Social could have used some theta bursts, the Auditory Signaling Processing Social never revved up the decibels, and the Thalamus Social was a little soporific when compared to the second AD karaoke night. Researchers trilled and warbled with varying levels of talent but with unstinting good humor, and those who did not even know the songs that they were being dragged to perform availed themselves of the lip-synch fake they originally cultivated in fifth-grade chorus. To the paparazzi who took snapshots of our esteemed colleagues, send them to firstname.lastname@example.org. We will post the pleasantly embarrassing photos (with permission) and keep the truly mortifying ones on file for future arm-twisting purposes.—Gabrielle Strobel and Tom Fagan.
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