11 Apr 2024

Phosphotau-217 has emerged as one of the most promising diagnostic markers of Alzheimer’s disease. It might also be a good therapeutic target, say scientists led by Yingjun Zhao at Xiamen University in China. In the March 20 Neuron, they reported that tauopathy mice given an antibody, dubbed mAb2A7, against p-Tau217 had fewer tangles, less neurodegeneration, and better memory and motor function. Their hippocampal proteome resembled that of wild-type animals.

“p-Tau217 is an interesting target because of its importance as an AD biomarker, and mAb2A7 looks promising for clinical development,” Einar Sigurdsson of New York University told Alzforum.

Jürgen Götz at the University of Queensland, Australia, also saw largely normalized brain proteostasis in tauopathy mice given an antibody to N-terminal tau called RNJ1. Still, the antibody barely reduced total or phospho-tau brain levels and did not improve motor control. These results were reported in a bioRxiv preprint uploaded on February 14. “Both studies provide evidence for the restoration of proteostasis as an underlying principle of tau immunotherapy,” Gotz wrote to Alzforum. “We believe tau antibodies should also be validated this way, rather than just focusing on changes to specific tau species, which is incompletely understood.”

Other scientists were skeptical that RNJ1 would be clinically useful. The field has moved away from N-terminal tau antibodies, such as AbbVie’s tilavonemab, Genentech’s semorinemab, and Biogen’s gosuranemab, because they fell short in trials for AD and progressive supranuclear palsy (Jun 2022 news; Nov 2021 conference news; Dec 2019 news).

Instead, antibodies targeting tau’s mid-region, including Roche’s bepranemab and Eisai’s E2814, have come to the fore in Phase 1 or 2 trials for AD as potential therapeutics (Mar 2021 conference news). Three other mid-domain or C-terminal tau antibodies in Phase 1 or 2 for AD target phosphorylated epitopes on the protein: Janssen’s JNJ-63733657 binds p-Tau217, Pinteon Therapeutics’ PNT001 recognizes p-Tau231, and Lundbeck’s Lu AF87908 latches onto p-Tau396/404.

For their part, co-first authors Denghong Zhang and Xuheng Gao at Xiamen University, Wei Zhang of China’s Fourth Military Medical University, and Chen Ming at the University of Macau generated mouse antibodies against mid-domain tau residues 209-223 phosphorylated at threonine 217. Of these, mAb2A7, bound tightest to p-Tau217 yet ignored non-phosphorylated tau. It also bound human tau within brain lysates from PS19 transgenic mice.

To test the antibody in vivo, the scientists dripped mAb2A7 into the noses of PS19 mice every three days for five months, beginning when the animals were 5 months old, when neuronal p-Tau217 puncta started forming in the hippocampus and piriform cortex. The 10-month-old treated mice clung for longer to a rotarod, spent more time studying novel objects, and found a hidden platform in a water maze more quickly than untreated mice, suggesting better coordination and memory.

Preventing Tangles. While the brain of a 10-month-old PS19 mouse was filled with AT8-positive puncta of p-Tau202/205 (left), barely any phospho-tau accumulated in mice given mAb2A7 (right). [Courtesy of Zhang et al., Neuron, 2024.]

The antibody slowed tangle deposition and spreading, neuroinflammation, and neurodegeneration. The antibody halved pathogenic p-Tau202/205 puncta, slashed ThioS-positive tangle load by 75 percent, and cut astro- and microgliosis in half in the hippocampi of 10-month-old mice (image above). Treated animals also had as many neurons and synapses as wild-types and wild-type-sized hippocampi (image below). In another treatment paradigm, mAb2A7 thwarted seeding of tangles when recombinant tau aggregates were injected into the hippocampus.

Preserving Neurons. Compared to hippocampal neurons (red) in wild-type mice (left), those in PS19 mice had withered by 10 months (middle). Mice treated with mAb2A7 beginning at 5 months maintained neuronal integrity (right). [Courtesy of Zhang et al., Neuron, 2024.]

Curious if the antibody has effects beyond tau, the researchers measured the hippocampal proteome from 10-month-old mice using mass spectrometry. From about 10,000 proteins, they found 2,146 up- or downregulated in PS19 mice compared to non-transgenic controls, most of which were involved in neurotransmission and synaptic signaling. Surprisingly, PS19 mice treated with mAb2A7 had almost identical proteomes to wild-type animals, with just 71 proteins differentially regulated.

When Zhang and colleagues homed in on the 2,146 dysregulated proteins in PS19 mice, they found that 1,391 were normalized after mAb2A7 (image below). Proteins involved in synaptic transmission and presynaptic endocytosis that had been downregulated in PS19s were upregulated after antibody treatment, while those involved in apoptosis and oxidative stress that had been upregulated were modulated down.

Proteome Protected. In PS19 mice, proteins (circles) whose levels were normalized by mAb2A7 support a variety of synaptic and signaling pathways. [Courtesy of Zhang et al., Neuron, 2024.]

All told, Zhao and colleagues concluded that p-Tau217 is not only a marker of pathology but is itself pathogenic, by increasing tangles and altering proteostasis. They have humanized mAb2A7 and will test its safety in nonhuman primates, Zhao told Alzforum.

Another Antibody, Same Protein Balance
Götz and colleagues also saw proteostasis mostly restored in mice after administering RNJ1. First author Esteban Cruz reported that the antibody, which binds residues 9-22 in tau’s N-terminus, reduced seeding of tau aggregates in HEK293 cells treated with extracts from rTg4510 mouse brain tissue by 70 percent. Likewise, it reduced seeding propensity of AD brain tissue extract by 40 percent.

Cruz and colleagues tested RNJ1 alongside the N-terminal tau antibody HJ8.5, the mouse version of tilavonemab, in 5-week-old K3 tauopathy mice. These animals overexpress the K369I tau mutant and develop motor problems by 4 weeks. They injected either antibody into the mouse peritoneum weekly for 14 weeks. At that point, mice given RNJ1 or HJ8.5 had 12 or 8.5 percent less total tau in whole brain lysates, respectively, than did untreated animals, though p-Tau202/205 levels were unchanged. Rotarod balance did not improve.

Still, RNJ1 normalized the brain proteome. Mass spectrometry of 6,600 proteins in whole brain lysates showed that, relative to wild-types, levels of 342 changed in untreated K3 mice. Of these, 177 were upregulated while 165 were less abundant. The former included microtubule-related proteins; the latter, proteins involved in metabolism and cellular respiration (image below). In K3 mice given RNJ1 or HJ8.5, 75 or 72.5 percent of those 342 proteins, respectively, reverted to wild-type levels, i.e., upregulated proteins decreased, and downregulated ones increased.

Up and Down in Tauopathy. Pathways relying on proteins that were downregulated (left) or upregulated (right) in K3 mice suggested changes in metabolism and respiration. Circle size indicates the number of proteins involved in each process, circle color is the p-value, and “GeneRatio” is the proportion of the 177 up- or 165 downregulated proteins in each pathway. [Courtesy of Cruz et al., bioRxiv, 2024.]

Similarly, the scientists found RNJ1 normalized phosphorylated proteins. While 541 phosphoproteins were dysregulated in K3 mice versus wild-type, 82 and 75 percent returned to wild-type levels after RNJ1 or HJ8.5 treatment, respectively. Restored proteins included those in the pre- and postsynaptic membranes.

“Our and Zhao’s proteomics results strengthen the importance of looking beyond changes in tau abundance and phospho-epitopes and instead incorporating (phospho)proteomics as a sensitive indicator of how cellular pathways are changing with tau immunotherapy,” Cruz told Alzforum.—Chelsea Weidman Burke

Comments

1. • Jürgen Götz
     The University of Queensland
   • Posted: 05 Aug 2024

   We are very pleased that our study uploaded on bioRxiv, on proteostasis as a fundamental principle of Tau immunotherapy, is now out in the journal Brain.

   References:

   Cruz E, Nisbet RM, Padmanabhan P, van Waardenberg AJ, Graham ME, Nkajja G, Tapaswi S, Connor BJ, Robinson P, Götz J. Proteostasis as a fundamental principle of Tau immunotherapy. Brain. 2024 Jul 29; Epub 2024 Jul 29 PubMed.

   View all comments by Jürgen Götz

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References

Therapeutics Citations

1. Tilavonemab
2. Semorinemab
3. Gosuranemab
4. Bepranemab
5. E2814
6. PNT001
7. Lu AF87908

News Citations

1. TAURIEL Phase 2 Data Published 17 Jun 2022
2. More Tau Antibodies Bid Adieu; Semorinemab Keeps Foot in Door 23 Nov 2021
3. Gosuranemab, Biogen’s Anti-Tau Immunotherapy, Does Not Fly for PSP 13 Dec 2019
4. N-Terminal Tau Antibodies Fade, Mid-Domain Ones Push to the Fore 27 Mar 2021

Research Models Citations

1. Tau P301S (Line PS19)
2. rTg(tauP301L)4510

Other Citations

1. JNJ-63733657

Further Reading

No Available Further Reading