Sang Ji

Background: The relationship between traumatic brain injury (TBI) and neurodegenerative diseases such as Alzheimer’s Disease (AD) has been studied extensively with pathological tau being implicated in their progression.^1,2 Specifically, hyperphosphorylated forms of tau propagate from initially focal deposits to more widespread grey matter.³ There has been difficulty in coming up with treatments for AD. One limitation is that most therapeutic approaches is designed to target Aβ without regard to tau.⁵ Given the ability of primordial misfolded tau to seed pathological features that develop into AD and other tauopathies, it stands to reason that novel treatments that target pathological tau may inhibit or even prevent the development of these diseases.²

Objective: To understand the therapeutic properties of Aβ1-6_A2V(D) in TBI derived AD.

Search Methods: Articles were found on PubMed using the key words “tauopathies”, “Aβ1-6_A2V(D)”, and traumatic brain injury” with the time frame of 2017 to 2026.

Results: Experiments were conducted to test Aβ1-6_A2V(D) therapy in 3 distinct conditions. The first condition tested the peptide’s effects on recombinant tau-P310L, a mutant form of tau that is especially prone to misfolding⁴. Aβ1-6_A2V(D) displayed inhibitory effects on tau-P310L aggregation in a culture of E. coli. Furthermore, when C. elegans were fed brain homogenates from P301 transgenic mice, those who were also fed Aβ1-6_A2V(D) were similarly protected.

The second condition tested the peptide’s effects on 3xTg-AD mice which harbor 3 transgenes making them more susceptible to developing AD. Administration of Aβ1-6_A2V(D) significantly reduced post-TBI memory impairment in TBI exposed 3xTg-AD mice as measured by Y-maze test. Similar to the experiment conducted with P301L transgenic mice, when C. elegans were fed brain homogenates from 3xTG-AD mice exposed to TBI, those that were also fed mice treated with Aβ1-6_A2V(D) did not present the same toxic effects as those fed with mice with no treatment. Notably, 3xTg-AD mice exposed to TBI and treated with Aβ1-6_A2V(D) had significantly reduced levels of Aβ compared to those without treatment. This reduction in amyloid burden may be a potential mechanism explaining the reduced toxicity seen in C. elegans.  The third condition tested the peptide’s effects on aged mice as they do not develop Aβ plaques unlike aged humans. This difference allows testing of whether Aβ1-6_A2V(D) can maintain protective qualities in the absence of Aβ pathology. TBI exposed mice demonstrated significant memory deficit as measured by Y-maze while Aβ1-6_A2V(D) treated mice demonstrated improved memory functions to levels on par with sham mice. Aβ1-6_A2V(D) additionally demonstrated protection against TBI axonal damage by significantly reducing plasmatic NfL levels. On biochemical analysis of their brain homogenates, mice treated with Aβ1-6_A2V(D) showed significantly reduced levels of phosphorylated tau and the ratio of phosphorylated tau to overall tau. Again, similar experiments were conducted, feeding C.elegans tissue from TBI exposed mice. Tissues from untreated mice caused reduced locomotor activity while tissues from mice treated with Aβ1-6_A2V(D) showed no effect on locomotor activity.

Conclusion: Aβ1-6_A2V(D) peptide demonstrates protective action against Aβ aggregation and tau pathologies in several tauopathy conditions in mice. Furthermore, these protective effects translated over to C. elegans fed with tissues of mice treated with Aβ1-6_A2V(D). Treatment with Aβ1-6_A2V(D) demonstrates promise in inhibiting the formation of pathological tau and the development of AD after exposure to TBI.

Works Cited:

1. Puangmalai N, Bhatt N, Bittar A, Jerez C, Shchankin N, Kayed R. Traumatic brain injury derived pathological tau polymorphs induce the distinct propagation pattern and neuroinflammatory response in wild type mice. Progress in Neurobiology. 2024;232:102562. doi:https://doi.org/10.1016/j.pneurobio.2023.102562
2. Edwards G 3rd, Zhao J, Dash PK, Soto C, Moreno-Gonzalez I. Traumatic Brain Injury Induces Tau Aggregation and Spreading. J Neurotrauma. 2020 Jan 1;37(1):80-92. doi: 10.1089/neu.2018.6348. Epub 2019 Aug 28. PMID: 31317824; PMCID: PMC6921297.
3. Zanier, E. R., Bertani, I., Sammali, E., Pischiutta, F., Chiaravalloti, M. A., Vegliante, G., Masone, A., Corbelli, A., Smith, D. H., Menon, D. K., Stocchetti, N., Fiordaliso, F., De Simoni, M.-G., Stewart, W., & Chiesa, R. (2018). Induction of a transmissible tau pathology by traumatic brain injury. Brain, 141(9), 2685–2699. https://doi.org/10.1093/brain/awy193
4. Dujardin, S., Bégard, S., Caillierez, R. et al. Different tau species lead to heterogeneous tau pathology propagation and misfolding. acta neuropathol commun 6, 132 (2018). https://doi.org/10.1186/s40478-018-0637-7
5. Diomede, L., Zanier, E. R., Moro, F., Vegliante, G., Colombo, L., Russo, L., Cagnotto, A., Natale, C., Xodo, F. M., De Luigi, A., Mosconi, M., Beeg, M., Catania, M., Rossi, G., Tagliavini, F., Di Fede, G., & Salmona, M. (2023). Aβ1-6_A2V(D) peptide, effective on Aβ aggregation, inhibits tau misfolding and protects the brain after traumatic brain injury. Molecular psychiatry, 28(6), 2433–2444. https://doi.org/10.1038/s41380-023-02101-3