Researchers know that soluble Aβ aggregates come in many shapes and sizes, but they have had trouble assigning specific effects to particular species in vivo and replicating those effects independently. In the June 4 Cell Reports online, researchers led by Karen Ashe at the University of Minnesota, Minneapolis, make another attempt. They distinguish between two broad classes of Aβ oligomers, reporting that type 1 and type 2 have distinct structures and behaviors. In mouse models, type 1 oligomers appear early, disperse widely through brain tissue, and correlate with subtle cognitive deficits. Type 2, on the other hand, have the structure of amyloid fibrils, appear only after plaques form, remain sequestered around plaques—and seem harmless to the mice. It is unclear if these data reflect what happens in human brains. Still, the findings highlight the importance of defining the specific oligomers present in Alzheimer’s, the authors suggest. This knowledge, coupled with information about antibody binding characteristics, might explain why some antibody therapies have worked better than others.
“I’m thrilled with this report. This is the clearest data yet showing that different oligomers have different pathological consequences,” said Charles Glabe at the University of California, Irvine.
Glabe was not involved in the research, but in previous studies he catalogued two general varieties of Aβ oligomer: those that have a parallel β-sheet structure similar to fibrils and bind the OC antibody, and those that have a distinct “prefibrillar” structure and bind the A11 antibody (see Kayed et al., 2007; Glabe, 2008). Later studies suggested that A11 recognizes β-sheets with an antiparallel, out-of-register conformation, in which every other strand travels in the reverse direction and amino acids do not line up (see Mar 2012 news; Liu et al., 2012).
Ashe wondered if these two oligomer classes might behave differently in vivo as well. To characterize them, first author Peng Liu prepared aqueous extracts from the brains of Tg2576 and hAPP-J20 mice of different ages. The former carry human APP with the Swedish mutation; the latter, Swedish and Indiana. For both models, the A11 antibody reacted with extracts from young and old mice, whereas OC only bound to samples from older, plaque-bearing animals. The authors then stained brain sections from Tg2576 (not the J20) mice with each antibody. OC lit up only dense-core plaques and their immediate surroundings, but A11 bound throughout brain tissue. This result highlights that the two types of oligomers appear at different times and places in the brain. The authors dubbed the A11 species type 1, and the OC variety type 2.
This study used A11 and OC binding to designate type 1 and 2 oligomers. It did not use biochemical or biophysical methods to characterize these species.
A third mouse model, rTg9191, expresses human APP with the Swedish and London mutations and develops plaques by 8 months of age (see Liu et al., 2015). In this model, type 2 oligomers again associated with plaques both temporally and spatially, but type 1 oligomers were absent at all ages. Because these mice express lower levels and a more amyloidogenic form of Aβ than the other models, the authors suspected that the expression level and amino acid sequence of APP might determine what kind of oligomers form. To test the idea that expression level matters, they used a fourth model, TetO-APPSweInd mice, in which transgene expression can be turned off. Switching off APP for five weeks in aged mice dropped type 1 oligomers by more than half, but type 2 oligomers remained stable. This confirmed that APP expression level affected each type differently, and that type 2 oligomers are more stable.
What effects do each type have on the brain? In earlier work, Ashe and colleagues traced memory deficits in Tg2576 mice to the presence of an A11-positive oligomeric species, Aβ*56 (see Mar 2006 news). Now classed as type 1, the presence of this 12-mer of Aβ correlated perfectly with cognitive problems in the other models as well, the authors found. The rTg9191 mice, which make no Aβ*56, performed a spatial memory or prefrontal behavioral task normally at any age. Likewise, turning off the transgene and thereby suppressing type 1 oligomers in TetO-APPSweInd mice has been reported to rescue cognition (see Fowler et al., 2014).
By contrast, type 2 oligomers caused no detectable deficits. Does this mean they are not toxic? To test this, the authors extracted type 2 oligomers from the brains of aged rTg9191 mice and injected them into the lateral ventricles of wild-type rats. The animals developed memory problems, forgetting a previously learned task. Type 2 oligomers can be toxic when dispersed through brain tissue, and are only innocuous in mice because they are sequestered around plaques, the authors concluded. Spatial distribution appears to be more important than quantity in determining toxicity, since type 2 oligomers make up about 95 percent of the total soluble Aβ in aged Tg2576 mice.
Overall, the data suggest a model in which Aβ can aggregate by one of two pathways, the authors propose. The peptide easily and quickly forms type 1 oligomers, but the 12-mers never grow into larger structures. Type 1 oligomers travel widely and therefore are most likely to interfere with synapses, leading to cognitive deficits. In the other pathway, Aβ more slowly forms parallel β-sheets that grow into fibrils and seed plaques. Once made, they persist. The plaque surface then catalyzes the formation of small, stable, type 2 oligomers with a parallel β-sheet structure similar to its own (see May 2013 news; Cohen et al., 2015). These oligomers remain confined to the vicinity of plaques, and therefore cause fewer cognitive problems. It is unclear what sequesters this species, though the authors speculate microglia may play a role.
Do these animal studies match what happens in people? Ashe and colleagues previously identified Aβ*56 in human brains, and reported that its levels rose with age, correlated with plaque load and pathological tau in early AD, but dwindled later in disease (see Lesné et al., 2013). In the present study, the authors measured plaque volume in postmortem AD brains, and found that plaque occupied 5 to 10 percent of the cortices. This is close to the plaque load in aged rTg9191 mice, which the authors calculated to cover 11 percent of the cortex. This suggests to Ashe that type 2 oligomers could be similarly restricted in human brains as in mice brains. Ashe said she will microdissect plaques and plaque-free regions from postmortem AD brains to test this question.
However, assuming that type 1 oligomers cause the cognitive decline associated with AD would be premature, Ashe said. She pointed out that the memory problems in mice are small, and might correspond to subtle cognitive deficits that crop up in preclinical stages of Alzheimer’s, not dementia. Dementia is characterized by massive neuronal loss, but neurons do not die in these mouse models. Perhaps there is some toxic ingredient missing in mice, such as human tau, Ashe suggested. In addition, plaques in human brains tend to form in the hubs of the default mode network, key nodes for neural communication (see Feb 2009 news). Thus, even if type 2 oligomers are confined to the vicinity of plaques, they might be able to disrupt this far-flung brain network, Ashe speculated. Connectivity in the DMN falters early in AD (see Nov 2007 news; Jul 2012 news). Further studies will be necessary to determine what kinds of cognitive problems each oligomer class causes in people, she added. Ashe also wants to nail down the fine molecular structure of the two classes, and determine which signaling pathways they activate.
Other researchers noted implications for antibody therapy. Lary Walker at Emory University, Atlanta, said future studies should determine how various therapeutic antibodies interact with different types of oligomers. This might explain why some antibodies work better than others. Ashe noted that bapineuzumab and gantenerumab both recognize fibrillar Aβ. In trials, these antibodies lowered plaque load but did not stem cognitive decline (see Sep 2012 conference news; Dec 2014 news). Aducanumab, which is reported to recognize Aβ oligomers, posted promising cognitive results in Phase 1 (see Mar 2015 conference news). Structural studies are beginning to decipher how various antibodies bind Aβ (see May 2015 news).
Distinct oligomeric species may also play a role in other protein-aggregation diseases. “This paper lays the groundwork for similar studies on other proteins implicated in neurodegenerative diseases, including α-synuclein, tau, TDP-43 and others,” Rakez Kayed at the University of Texas Medical Branch at Galveston wrote to Alzforum (see full comment below).—Madolyn Bowman Rogers
- Anti-parallel Universe—Rare Amyloid Peptides in Cylinders, Sheets
- Aβ Star is Born? Memory Loss in APP Mice Blamed on Oligomer
- Aβ Fibrils Drive Oligomer Formation, New Model Suggests
- Cortical Hubs Found Capped With Amyloid
- Functional Imaging Gives Early Glimpse of AD
- Communication Breakdown: Multiple Networks Decline in AD Brains
- Bapineuzumab Phase 3: Target Engagement, But No Benefit
- End of the RoAD for Gantenerumab? Roche Declares Prodromal Alzheimer’s Trial Futile
- Biogen Antibody Buoyed by Phase 1 Data and Hungry Investors
- Shape of a Hug: How the Embrace of a Therapeutic Aβ Antibody Really Matters
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