CONFERENCE COVERAGE SERIES
Society for Neuroscience Annual Meeting 1998
Los Angeles, California, U.S.A.
07 – 12 November 1998
1998 Society for Neuroscience Meeting: α2-Macroglobulin
Presented by Rudy Tanzi. AD is now widely considered to be a multifactorial disease with only a few dominant genetic mutations that can be considered as directly causing the disease, i.e., APP and the presenilins. The majority of genetic loci are likely to play broader, but less specific roles, in the disease and are commonly grouped together as "risk factors."
Dr. Tanzi reviewed the evidence from his group for a genetic association between AD and the gene encoding for α2-macroglobulin (A2M), a broad-spectrum protease inhibitor that is present in brain and plasma. The approach involved a family-based "sibship" analysis (exluding individuals younger than age 50 since they are more likely to represent familial forms associated with APP or the presenilins). The evidence strongly supports (p.00009) an increased incidence of a specific deletion affecting the α2M gene in affected siblings with no effect on age of onset. He noted that other groups had failed to find a similar linkage using "case-control" studies and suggested that this is probably due to the fact that identification of genes having subtle effects on disease risk are likely to be masked by population admixture. Family-based studies avoid this problem by effectively controlling for genetic background. He suggested that future studies will need to take this into consideration in order to unravel the complex nature of diseases for which many genes may contribute risk.—Keith Crutcher
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1998 Society of Neuroscience Meeting: AD Plaques Associated with Curvier Dendrites
Are both Aβ and the intracellular hyperphosphorylation of tau necessary for the induction of morphological alterations in dendrites in AD? What effect might abnormally shaped dendrites have on synaptic transmission? Using triple labeling for neurofilament (SMI-32), hyperphosphorylated tau (Alz-50) and β-amyloid (R1280), Robert Knowles, Brad Hyman and colleagues addressed these hypotheses via confocal microscopy (abstract 107.8). In nondemented brains, they found that the morphology (curvature and curvilinear length) of neurofilament-positive, Alz-50-negative dendrites which pass through plaques were unaffected by the presence of Aβ deposits. In the AD brain, these same neurofilament-positive, Alz-50-negative dendrites exhibited a threefold increase in curvature when within Aβ deposits. When dendrites were both Alz-50-positive and within Aβ deposits, their curvature increased fourfold and their curvilinear length was increased by 31 percent. These measurements allow for an analysis of the functional consequences of such alterations using "Genesis" cable property computer simulations. The net result: a 30 percent delay in synaptic transmission. Considering the integration and timing necessary within large-scale neural networks, such delays within even a subset of dendrites could have serious impact on function.
What accounts for these changes in dendritic morphology? It appears that Aβ alone is not enough; dendrites in the non-demented brains were unaffected by plaques. The likely culprit is a loss of normal function in hyperphosphorylated tau. However, even Alz-50 negative dendrites exhibit abnormal morphology if they are within AD plaques (but not non-AD plaques). Are there other components of AD plaques which are absent from the plaques in non-demented brains (e.g., extracellular matrix components, complement proteins, etc.) which could account for the morphological changes? Another possibility is that Alz-50 is not sensitive enough to detect all tau hyperphosphorylation. Earlier markers such as AT8 and MC1 might reveal abnormal tau within plaque associated dendrites. Paul Coleman asked how to reconcile these data with previous reports that dendritic length in AD is decreased compared to controls. Knowles responded that these data were within-subject measures rather than comparisons between AD and control, while acknowledging that differential shrinkage between diseased brains and controls is also possible.
One also has to wonder whether changes in synaptic transmission in the dendrites within AD plaques would really affect processing. As dendritic spike timing became delayed, couldn't the aged brain compensate for these changes? Brad Hyman responds that these timing changes would be essentially random within a large network. While an individual neuron might compensate for increasing delays within one branch of a circuit, there would be no way for an entire network to compensate for small delays from multiple sites. So even if there are "healthy appearing" neurons within the AD brain, their dysfunction could be contributing to AD long before they become neurofibrillary tangles.—Brian Cummings
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1998 Society for Neuroscience Meeting: Aβ vs. APP Effects in Transgenics
Hopefully, transgenic AD models will be more useful than just demonstrating that the overexpression of mutant human APP can lead to the deposition of Aβ plaques. Several groups are now asking, what are the functional consequences of the overexpression of mutant APP on neurophysiology? Are any changes in transmission due to signaling via APP itself or via AHopefully, transgenic AD models will be more useful than just demonstrating that the overexpression of mutant human APP can lead to the deposition of Aβ plaques? Recording in hippocampal slices from Tg mice expressing APPind, APPlon or APPswd mutations, Albert Hsia and colleagues report severe impairments in extracellular field potentials between CA3 and CA1 (Abstract 285.5). Higher stimulation was needed to elicit a synaptic response. However, LTP in APPind mice was normal. They also found that an increase in the secretion of AHopefully, transgenic AD models will be more useful than just demonstrating that the overexpression of mutant human APP can lead to the deposition of Aβ plaques was related to the extent of synaptic transmission deficits. To address whether these changes were a result of AHopefully, transgenic AD models will be more useful than just demonstrating that the overexpression of mutant human APP can lead to the deposition of Aβ plaques itself, or a consequence of the overexpression of APP, they crossed APPind mice with the APPswd mice, which results in twofold increase in AHopefully, transgenic AD models will be more useful than just demonstrating that the overexpression of mutant human APP can lead to the deposition of Aβ plaques (Citron, 1992) but similar basal levels of APP. In these mice, there is an additional twofold decrement in synaptic transmission, suggesting that Aβ is responsible. However, Steve Barger pointed out that while holo APP levels may be the same, Hsia et al. measured sAPPα levels in the different lines, and sAPPα was severely decreased in the APPind/APPswd crossed mice. Thus, deficits in synaptic transmission may not be due to Aβ itself but could also be the result a loss of function from sAPPα. These results look promising, but further work is need to dissociate the role of APP from Aβ.—Brian Cummings
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1998 Society for Neuroscience Meeting: Frameshift Mutations Precede Tangles, Plaques in DS
Fred van Leeuwen and his research group presented new data regarding their molecular misreading hypothesis for sporadic AD (Abstract 107.7). The molecular misreading hypothesis suggests that the inaccurate conversion of genomic information into mRNA and subsequent translation of nonsense proteins, particularly as a result of dinucleotide deletions, may be a causative event in sporadic AD. The authors examined immunoreactivity for antibodies directed against the APP+1 frameshift mutation in the brains of cognitively impaired and cognitively normal individuals with Down's syndrome as a model of the early stages of the progression of AD pathology, and reported that immunoreactivity for APP+1 is present in the absence of other neuropathological indicators, including neurofibrillary tangles and Aß deposition, in nondemented DS cases. This suggests that dinucleotide deletions in APP transcripts are an early event in AD pathogenesis, not merely a result of other pathogenic processes.
This data may conflict with published findings demonstrating immunoreactivity for Aß deposition in nondemented DS individuals as young as their teens (van Leeuwen did not detect Aß within their young DS cases). However, a complete comparison of these markers will yield additional insight in the future. These data represent a preliminary step in evaluating the potential of these missense mutations to cause neurofibrillary tangle formation, the accumulation of Aß, or other neuropathological events characteristic of AD neurodegeneration. These data add to the interesting hypothesis of molecular misreading in sporadic AD.
In other work presented at the SFN meeting, van Leeuwen's group reported evidence that the same mutant RNAs detected in AD and DS brain can be detected in human neuronal cell lines, suggesting that the aberrant synthesis of missense proteins may be a common event in highly transcriptionally active cells. In current work, Dr. van Leeuwen is developing a transgenic model overexpressing these missense mutants to further address the molecular misreading hypothesis.—Aileen J. Anderson
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1998 Society for Neuroscience Meeting: Complement Cascade Activation by Neurofibrillary Tangles
The complement cascade is a complex inflammatory process that can mediate diverse functions, from targeting cells and cellular components for phagocytosis to membrane attack complex-mediated cell death. In this context, there are 20 or more individual proteins that participate in the complement cascade. Immunoreactivity for a wide variety of complement proteins, e.g., C1q and the terminal membrane attack complex (MAC or C5b-9), has been reported in association with both β-amyloid plaques and neurofibrillary tangles (NFT) in AD brain. Previous work by several laboratories, including that of Joseph Rogers and Andrea Tenner, has demonstrated that β-amyloid 1-42 can activate complement and bind complement proteins including the C1q A chain. In a newer study, Rogers et al. report that a purified fraction of isolated NFTs can also activate a complement response (Abstract 502.10). Recombinant tau also activated terminal complement in a dose-dependent manner nearly as efficiently as synthetic Aβ 1-42. Further, a fraction of isolated tau that formed fibrils, as compared to soluble recombinant tau, activated complement even more strongly. These data may suggest that both β-amyloid plaques and NTFs could serve as chronic mediators of an inflammatory response in the AD brain.—Aileen Anderson
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1998 Society for Neuroscience Meeting: Untangling Tau Phosphorylation
Aβ peptide has dominated center stage in AD research, but the discovery last year of a tau mutation that causes a familial non-AD dementia has reawakened broader interest in tau. In Alzheimer’s disease, tau aggregates into pathological neurofibrillary tangles as a result of hyperphosphorylation. One theory attracting attention is the idea that tau becomes hyperphosphorylated due to a reactivation of cell cycle machinery in neurons.
Advocates of this view include Eva-Maria and Eckhard Mandelkow, who presented a cluster of papers further teasing apart the mechanisms that underlie tau phosphorylation (Abstracts 502.2-4). According to their data, MARK (microtubule affinity regulation kinase) phosphorylates tau at Ser262, which causes tau to detach from microtubules, thereby destabilizing them. The Mandelkows think that normally, destabilization allows neuronal processes to become dynamic and form new extensions. "Phosphorylation is a GOOD thing," is how Eva-Maria Mandelkow put it. They identified the KXGS repeat domain as the site which, if slightly phosphorylated, increases process outgrowth.
The Mandelkows went on to elucidate a phosphorylation pathway that gives rise to the Alzheimer's form of tau, as identified by the AT100 antibody. They reported that GSK3-β, acting on a PHF-like conformation of tau, followed by phosphorylation by PKA, is the only pathway that produces AD-type tau.
Finally, Eckhard Mandelkow described some preliminary findings indicating that tau may play a role in axonal transport. He sketched out a model in which tau, depending on its state of phosphorylation, may alter the equilibrium state of axonal transport. For example, he speculated, if the rate of retrograde transport were to outstrip that of anterograde transport, important molecules will not be able to reach the axon terminals.—June Kinoshita
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Papers
- De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 1999 Apr 8;398(6727):518-22. PubMed.
1998 Society for Neuroscience Meeting: Alois Award Winners
The organizers of this year's special interest social on Alzheimer's disease decided to stage an awards ceremony to salute scientists who had distinguished themselves in various categories not ordinarily recognized by the committees of better-known scientific prizes. Although few Hollywood celebrities, if any, were to be spotted at the event, the Alois Awards shared many similarities with an analogous film-industry ceremony that takes place annually a few blocks up the avenue from the L.A. Convention Center, including the aura of secrecy surrounding the winners (whose names were concealed within sealed envelopes), the prize (a small golden statuette of a humanoid form), and the employment of two individuals who resemble Billy Crystal as much as anyone else in the field: Dale Schenk and Rudy Tanzi (stepping in at the last moment for a mysteriously AWOL John Hardy). This year's prizes bring a welcome breath of self-directed humor in a field that badly needs it. And the winners were:
Best Highlighted Yet Confusing Research Topic
-Sam Sisodia for Presenilin
Best Resurrected Research Topic
-The Mandelkows, on behalf of the Whole Tau Community
Best Elaborate Research Topic
-Rudy Tanzi for α2 Macroglobulin
Boldest Choice for an AD Transgenic Spokesmodel
-Matthias Staufenbiel et al.
Most Slides Ever Shown in a 12-Minute Neuroscience Presentation
-Dora Games (60 slides)
Best Persistent Research Topic
-Dennis Selkoe for β-Amyloid
Most Thoroughly Beaten Research Topic
-Steven Younkin for Aβ42
Person Most Responsible for Consolidating Support for the Amyloid Hypothesis
-Allen Roses
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1998 Society for Neuroscience Meeting: Amyloid Plus Astrocytes Thwarts Axon Regeneration
The regulation of neuronal plasticity and regeneration in the CNS is an aspect of Alzheimer’s disease that often has to compete with the big stars, such as amyloid or presenilin, for attention. Yet, it is clear that understanding the factors that regulate axonal growth and the formation and maintenance of connections between neurons is an important part of any approach to AD and other neurodegenerative diseases. The study of axonal regeneration is largely the purview of investigators who do not necessarily have neurodegenerative diseases in mind. Yet the approaches taken, and the biological questions asked, are often related.
A good example of this was provided in the symposium talk given by Dr. Jerry Silver of Case Western Reserve University, Cleveland, who has made a number of contributions to the study of factors involved in promoting, or inhibiting, regrowth of axons in the mature mammalian CNS. His presentation focused on work carried out over the past couple years in which the potential for regeneration within the mature mammalian brain has been dramatically demonstrated through the use of microtransplants of dorsal root ganglion neurons into major white matter fibers tracts (e.g., the corpus callosum) of the mature rat brain. Long-distance regeneration, extending for up to several millimeters, was found in those cases where there was no evidence of glial activation in the area of the transplant. Conversely, regenerating axons stopped when encountering zones of increased expression of chondroitin sulfate. In a search for stimuli that might serve to activate astrocytes, one of the most effective agents was found to be amyloid. In fact, astrocytes cultured on amyloid spots reacted by producing a complex substrate that included chondroitin sulfate—a substrate that was hostile to neurons subsequently cultured on the same spots. Enzymatic digestion of the chondroitin sulfate neutralized the hostile substrate. The amyloid spots without astrocytes were also otherwise permissive for neuronal growth. In light of the demonstrated presence of proteoglycans in plaques, these results suggest that similar phenomena may underlie some of the neuritic pathology in AD.
Although the focus of Dr. Silver’s talk was on the relevance of these findings to the promotion of long-distance axonal regeneration in the injured mammalian spinal cord, a dramatic result that will certainly stimulate renewed optimism for the eventual restoration of function following spinal cord injury, the same principles may have direct relevance to understanding the local regulation of neurite growth in the vicinity of the AD plaque. It is this type of synergy across disciplines and models that represents some of the most abundant fruit to be harvested from an interdisciplinary approach to the study of neuroscience.—Keith A.Crutcher
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1998 Society for Neuroscience Meeting: Enhancement of Pathology in PS1/APP Tg Mice
There have been several reports over the years that the AD brain exhibits deficits in energy metabolism. In 1994, Yankner's group reported that sodium azide treatment increased the processing of APP to potentially amyloidogenic fragments in culture. Paul Jantzen and colleagues report (Abstract 592.7) on the effects of NaAz administrationin PS1/APP (Duff/Hsiao) mice. Following four weeks of administration of NaAz (via subcutaneous infusion pump), they found that cytochrome oxidase activity was reduced by 22 percent. In untreated double Tg mice, they see relatively few activated microglia (detected with F480) associated with Aβ deposits, but in the NaAz treated animals, there is an extensive upregulation of microglia around Aβ deposits. The group did not report an increase in microglia associated with Aβ deposits in untreated Tg animals, in contrast to other studies. However, the association of activated microglia in the NaAz-treated animals mirrored that typically seen in moderately severe AD cases, and was more extensive than I've seen in any transgenic model. Also, they reported the presence of TUNEL-positive nuclei in the NaAz-treated Tg mice, while infusion of NaAz into non-Aβ depositing littermates did not active microglia nor result in significant numbers of TUNEL positive nuclei. Presumably, these littermates were nontransgenic, but this was not clear from the presentation. Jantzen did not present data addressing whether NaAz treatment actually leads to greater deposition of Aβ itself, as one might predict. It is encouraging that many labs are now moving to phases where different systems within these Tg models are challenged (e.g., see also Abstract 592.6).—Brian J. Cummings
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1998 Society for Neuroscience Meeting: Inflammatory Mechanisms in Transgenic Models of AD
Since the development of transgenic models of β-amyloid plaque formation, considerable debate has developed over the apparent paucity of neuronal cell loss found in the majority of these models. One hypothesis for why there is an overall lack of neurotoxicity in these models is that mice overexpressing βAPP are unable to mount an efficient inflammatory response to the overproduction of the Aβ peptide. Previous work has shown that the β-amyloid peptide activates the complement cascade by binding to the A chain of C1q, a collagen-like region of this molecule that typically mediates non-antibody-mediated complement cascade activation. In a study presented by David Cribbs, the ability of mouse C1q to bind human Aβ peptide and activate a complement response was examined (Abstract 592.8). Sequence analysis revealed that the mouse C1q A chain is missing two of the three arginine residues that are essential for complement activation by the human C1q A chain. Further, biochemical data demonstrated that approximately twice as much Aβ peptide is required by mouse C1q as is required by human C1q for equivalent complement activation. This observation does not reflect a general deficiency of mouse complement, as the antibody-dependent activation of mouse C1 is actually more efficient than that in the human.
These data may suggest that additional modifications of the mouse genome may be necessary to mimic the activation of inflammatory mechanisms by the Aβ peptide observed in the human Alzheimer's brain. An additional presentation on this topic by K. L. Wright (Abstract 592.9) supports this contention. In this work, the complement sufficiency of PS1/APP double transgenic mice was enhanced by backcrossing onto a BUB/BnJ background. The BUB/BnJ mouse strain has been shown to exhibit a much greater capacity for complement activation than other mouse strains. First-generation backcross mice exhibited a dramatic increase in microglial response to congophilic Aβ deposits and an overall increase in microglial response in cortex as observed by the distribution of immunoreactivity. No change in either Aβ deposition or GFAP staining was noted. Further studies may yield additional insights into the importance of inflammatory mechanisms in AD pathogenesis.—Aileen Anderson
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1998 Society for Neuroscience Meeting: Lesion Lops Aβ Deposition
The Athena Neuroscience PDAPP transgenic mice develop heavy Aβ deposits, particularly in the outer molecular layer (OML) of the dentate gyrus, a region that receives nerve projections from the entorhinal cortex. Theorizing that neuronal inputs from the entorhinal cortex might somehow drive the production of Aβ, Karen Chen and colleagues at Athena performed unilateral electrolytic lesions of the EC in mice at various ages and examined them at intervals over several months to see what effect the lesions had on Aβ deposition in the OML (Abstract 592.6). Sham lesions were performed on a group of age-matched control animals. Chen et al. reported that mice lesioned at 8.5 and 10.5 months showed a marked decrease in Aβ deposits on the lesioned side, when they were examined several weeks and months later. The effect occurred as rapidly as two weeks later (in mice lesioned at 10.5 months and examined at 11 months) and lasted at least 4.5 months (in mice lesioned at 8.5 months and examined at 13 months). Notably, mice that were lesioned at 15.5 months did not show a loss of amyloid deposition when they were sacrificed two weeks later. This intriguing but preliminary study suggests a number of possible explanations. Perhaps the lesioning triggered inflammatory processes that clear the deposits, but which become less effective with age. Or the loss of entorhinal inputs may slow down deposition sufficiently to allow endogenous clearance mechanisms to remove the preexisting deposits. It remains for follow-up studies to determine the mechanisms underlying this striking effect.—June Kinoshita
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1998 Society for Neuroscience Meeting: ApoE Knockouts Unaffected in APP Expression and Processing
The critical role of ApoE in β-amyloid deposition was demonstrated last year by Eli Lilly scientists, who crossbred APP/PS1 transgenics with an ApoE knockout and found that these mice do not develop thioflavin S-positive deposits of fibrillar Aβ. In a series of follow-up studies (Abstract 592.5), Kelly Bales and colleagues examined older mice, up to 22 months of age, and found that these animals continue to remain free of fibrillar Aβ. Additional studies showed that the ApoE knockouts did not differ from ApoE-positive mice in their levels of APP expression or processing of APP. Although these data suggest that ApoE plays a direct role in facilitiating Aβ deposition, Bales cautioned that "gene rescue experiments using the three human isoforms of ApoE will be required to confirm this hypothesis.—June Kinoshita
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