Aggregation of minuscule amounts of Aβ peptides marks the beginning of Alzheimer’s disease. Can this clustering be stopped? In the November 16 Nature Neuroscience, scientists reported that of five immunotherapies that have been tested clinically, aducanumab best reduced seeding and propagation of Aβ plaques—at least in mice. Targeting these seeds as early as possible is crucial to thwarting AD onset, according to scientists led by Mathias Jucker, University of Tübingen, Germany. Jucker and colleagues found that injecting mice with aducanumab daily for five days led to a significant reduction of seeding potential six weeks later.

  • Mice were injected with several antibodies to neutralize Aβ seeds.
  • Aducanumab reduced seeding by almost 90 percent.
  • Seeds were present before any signs of amyloidosis.

“The paper convincingly demonstrates the presence of early Aβ seeds that can be removed, thereby suppressing Aβ deposition much later on,” Lars Lannfelt, Uppsala University, Sweden, told Alzforum. “It suggests that early seeding is a slow process and that it takes a long time to regenerate seeds if they are removed,” he added. Lannfelt, who developed the BAN2401 antibody that selectively binds to Aβ protofibrils, was not involved in this work. 

Studying amyloid aggregation presents a challenge because only a teeny fraction of Aβ monomers spontaneously form seeds. Over the years, researchers in Jucker’s lab have perfected amyloid seeding assays, where they test if minuscule samples of brain tissue or other source of Aβ seeds can accelerate amyloidosis in mice prone to develop plaques (Oct 2011 news; Sept 2013 news). Co-first authors Ruth Uhlmann, Christine Rother, and colleagues used the same principle to test how murinized versions of human Aβ antibodies aducanumab, gantenerumab, solanezumab, crenezumab, and donanemab could prevent plaque seeding in the very early stages of disease.

The researchers used 6-month-old APP23 transgenic mice. These animals do not begin to develop visible plaques until they are about 9 months old. Uhlmann injected the antibodies once a day for five days, then analyzed the rodent brains six weeks later. She found that only aducanumab had suppressed levels of insoluble Aβ42 in brain homogenates.

What about Aβ seeds? To test for those, the researchers injected some of the same homogenates into the brains of 3-month-old APP23 mice, then examined their brains eight months later. Homogenates from control APP23 mice had seeded amyloid plaques throughout the animals’ hippocampi, but homogenates from aducanumab-treated donor mice barely seeded any plaques (see image below). In effect, murinized aducanumab had reduced the seeding capability of the mouse brain homogenates by more than 80 percent. The authors did not test homogenates from mice injected with the other antibodies.

Seedless. When injected into 3-month-old APP23 mice, brain homogenates from 7.5 -month-old animals seeded rampant amyloidosis in the hippocampus over the next eight months (bottom). Mice injected with homogenates from aducanumab-treated mice had markedly less Aβ deposition (top). [Courtesy of Uhlmann et al., 2020 Nature Neuroscience.]

Why does only aducanumab reduce Aβ seeds? To address this, Uhlmann and colleagues profiled the types of Aβ assemblies each antibody bound. Because the structures of Aβ seeds have never been determined, the researchers relied on size fractionation. They found that in the brains of 26-month-old APP23 mice, which have rampant amyloid plaques, solanezumab, gantenerumab, and crenezumab recognized a variety of species, including smaller oligomers and monomers. In contrast, aducanumab and donanemab specifically recognized high-molecular-weight species. This profiling suggested that aducanumab might be better at binding Aβ seeds that pop up earliest in disease.

Analysis of 6-month-old APP23 mice supported this idea. Aducanumab detected nothing in brain homogenates, which the authors attributed to a paucity of seeds in these young mice. In contrast, solanezumab, gantenerumab, and crenezumab again detected smaller Aβ species. When Uhlmann concentrated the Aβ by immunoprecipitation, she picked up a signal with aducanumab.

“The beauty of aducanumab is that, at least in this study, it is highly selective at targeting larger oligomers, or small aggregates,” said co-author Lary Walker, Emory University, Atlanta. Walker thinks this has implications for therapy. “The thinking is that monomers present in the brain are distracting other antibodies from what they really need to bind to—the Aβ seeds.”

Because the antibody treatment only lasted five days and the brains were not sampled for another six weeks, Jucker and Walker believe that once aducanumab neutralizes the seeds, it takes time for new ones to form, thus delaying amyloid formation.

This is not the first time scientists have discovered that different antibodies can prevent Aβ fibrillization in different ways. In September, researchers from Lund University, Sweden, reported that solanezumab, bapineuzumab, gantenerumab, and aducanumab, interfered with different steps of the aggregation process (Sept 2020 news). Aducanumab was better able to prevent a process called secondary nucleation, which is how many oligomers or seeds are formed. Jucker and colleagues believe that aducanumab also binds to seeds that form from primary nucleation, which is a much rarer event. In fact, they were able to neutralize seeds that had formed before any plaques were detectable by histology.

“This demonstrates that therapeutically targetable, pathogenic Aβ seeds already exist during the lag phase of protein aggregation in the brain,” write the authors. “Thus, the preclinical phase of Alzheimer‘s disease—currently defined as Aβ deposition without clinical symptoms—may be a relatively late manifestation of a much earlier pathogenic seed formation and propagation that currently escapes detection in vivo.”

Whether aducanumab might similarly reduce seeding in the human brain remains to be determined. “Before we can figure that out, we must find biomarkers for the pre-amyloid phase, which will take time,” said Jucker. In the meantime, Biogen Inc., Cambridge, Massachusetts, has file for approval for aducanumab and awaits a decision from the Food and Drug Administration. At a November 6 advisory committee meeting, none of the 11-person panel believed the evidence was strong enough for approval (Nov 2020 news).—Helen Santoro

Comments

  1. I hope that this experiment can be repeated in a human CD33 transgenic mouse that has been crossed into an Alzheimer's model. There is strong unpublished evidence to suggest that CD33 is involved in the regulation of the phagocytosis or trogocytosis of neurotoxic, minuscule synaptic amyloid seeds within the synaptic space. There are several CD33 antibodies that have had safe profiles in clinical trials that could be tried, such as lintuzumab or gemtuzumab. It is possible that a combination of one of these and aducanumab might be effective at very early stages of the disease.

  2. Suppressing or slowing the progression of AD is thought to be a pathological condition shown in the reference paper. It has been shown that even if Aβ is deposited, disease onset can be suppressed or delayed by suppressing the spread of tau pathology. This suggests that there is little association between Aβ deposition and AD progression.

    Anti-Aβ antibodies are thought to work effectively against Aβ amyloidosis, reducing Aβ amyloid. Amyloid deposition at synapses will decrease and transmission will improve. It is thought that some improvement in cognitive function can be seen, but it may not be effective in the progression of AD.

    References:

    . Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report. Nat Med. 2019 Nov;25(11):1680-1683. Epub 2019 Nov 4 PubMed.

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References

Therapeutics Citations

  1. Aducanumab
  2. BAN2401
  3. Gantenerumab
  4. Solanezumab
  5. Crenezumab
  6. Donanemab

News Citations

  1. Seeds of Destruction—Prion-like Transmission of Sporadic AD?
  2. Does Aβ Come In Strains? Glimpse Into Human Brain Suggests Yes
  3. Of Four Aβ Antibodies, Only Aducanumab Stems Tide of Toxic Oligomers
  4. FDA Advisory Committee Throws Cold Water on Aducanumab Filing

Research Models Citations

  1. APP23

Further Reading

No Available Further Reading

Primary Papers

  1. . Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life. Nat Neurosci. 2020 Dec;23(12):1580-1588. Epub 2020 Nov 16 PubMed.