V24P Peptide Targets Amyloid Plaques in Alzheimer’s Disease

 A Novel Peptide Targeting Amyloid Plaques in Alzheimer’s Disease

Alzheimer’s Disease (AD) has been investigated for many years, searching for a cure. One of the most studied hypotheses is the amyloid cascade, which proposes that the amyloid-β protein has a crucial role in starting the AD progression.[5] Amyloid-β originated from the amyloid-β precursor protein.[5] Different enzymes snip off the amyloid-β precursor protein, resulting in the liberation of varying amyloid-β peptides.[5] In a healthy individual, the resulting peptides no longer needed for the functioning of cells are degraded.[2]

On the contrary, the self-aggregation of the resulting peptides is well known to start the pathogenesis of AD.[1] The production of excessive amyloid-β peptides induces neuronal cell death.[3] High levels of these proteins also affect the synaptic process, increase neurotoxicity and neuronal loss, and decrease neuroplasticity. [2,3] All these molecular processes are reflected in the AD patients’ symptoms, like memory loss, sleep problems, poor judgment, repeating questions, losing track of dates, and forgetting recently learned information.

Studies have shown that amyloid-β peptides like Aβ40 and Aβ42 are the principal composition of the amyloid-β plaques found in patients’ brains with AD postmortem.[3] Both Aβ40 and Aβ42 are very toxic species when they accumulate in the brain, affecting the well-functioning neurons. [1-3] For this reason, Aβ40 and Aβ42 are the most critical isoforms when studying AD pathology. In general terms, Aβ42 is known to form fibrils quicker than Aβ40.[3] Even though both have similar chemical composition, the aggregation of Aβ40 is mainly near cerebral blood vessels, and the Aβ42 isoform will be found in more quantities where the amyloid-β plaques are more concentrated in AD patient’s brains.[5]

Recently, investigators developed “an Aβ40 mutant peptide” called V24P (10-40).[3,4] In this case, the V24 in the original Aβ40 sequence was substituted by a D-form proline.[4] This single substitution alters the accumulation behavior of Aβ40. [3,4] After this modification, they found that V24P (10-40) decreases the cytotoxicity of Aβ40.[3,4] Also, V24P (10-40) shows a high affinity for β species signal.[3] In other words, V24P (10-40) can act like a molecular sponge (scavenger peptide) for Aβ40 isoforms, trapping these amyloid β fragments, thus avoiding self-aggregation (see Fig. 1).[3] V24P (10-40) promotes the degradation of amyloid β isoforms after trapping them.[3,7] This peptide was tested in AD mice models, which helps decrease the aggregation and toxicity of Aβ40 in the brain.[3,7] Researchers have pointed out that not all molecules with amyloid-β affinity can be reduced nor avoid the assembly of the amyloid protein in the brain.[4] This can explain different peptides like the D1 that, even though they have the affinity to amyloid-β, cannot help reduce the quantities of this protein in AD models.[3]

To improve the performance of the novel peptide, the investigators decided to add a conjugated PEI green fluorescent protein capable of entering the brain when administered intranasally.[3,6] The PEI fragment of the peptide increases the molecular sponge capacity of the V24P (10-40) PEI since this fragment has been studied in the past years, demonstrating the ability to absorb different molecules like DNA, pharmaceutical molecules, and proteins.[3] PEI has been used to develop gene therapy, drug delivery cell culture, protein aggregates inhibitors, and self-healing materials.[3,4,7] Several articles demonstrated that PEI can also interact with amyloid-β, reducing its toxicity.[3] The resulting V24P (10-40) PEI peptide is more efficient and resistant.3,4] Additionally, the PEI helps decrease the probability of self-aggregation of the V24P peptide.[3]


Mechanism of the V24P (10-40) scavenger peptide.

Figure 1.

Several studies show that V24P (10-40) PEI decreases the accumulation and toxicity of both Aβ40 and Aβ42 in the hippocampus and the cortex of AD mice models (see Fig.2).[3,5] V24P (10-40) PEI peptide also significantly decreases the amyloid-β plaque aggregation in AD mice models.[7] It is well known that amyloid-β plaques and neurofibrillary tangles tend to accumulate in the olfactory bulb, damaging olfaction in the early stages of AD. [3] This novel peptide demonstrated that it could reduce both plaques and neurofibrillary tangles in the olfactory bulb.[3,6] For this reason, the V24P (10-40) PEI peptide is an excellent candidate for preventing the pathogenesis of AD from its early stages.[1-4]

After testing different quantities (mg) of V24P (10-40) PEI, the investigators found that administering 1.6mg 6 times a week for eight months can reduce the amyloid-β in the hippocampus by 81%.[3] When comparing those results with other peptides made specially for decreasing the amyloid-β in the hippocampus, V24P (10-40) PEI shows the best performance (see Table 1).[3] Several studies suggest that V24P (10-40) PEI has excellent potential in slowing down the pathogenesis of AD by trapping and eliminating the overexpressed amyloid-β peptides in the olfactory bulb, hippocampus, brain cortex, and other possible areas.[2-4] AD is known to be a multifactorial disorder. However, a large percentage of patients show amyloid-β aggregation postmortem.[5] V24P (10-40) PEI is one of the few peptides tested in vivo, showing excellent results in decreasing self-aggregate proteins in the brain. [3,6] Stabilizing the amyloid-β levels in the brain can reduce neuronal cell mortality and memory loss, decreasing the chances of developing AD. [2]


Results of the Aβ40 and Aβ42 levels in the (a) hippocampus and (b) the cortex after the administration of V24P (10-40) PEI peptide

Figure 2.


  1. Burnouf, S., Gorsky, M. K., Dols, J., Grönke, S., & Partridge, L. (2015). Aβ 43 is neurotoxic and primes aggregation of Aβ 40 in vivo. Acta neuropathologica130, 35-47.
  2. Chen, R. P. Y. (2017). Design and Application of Anti-Amyloid Peptide-Based Inhibitors as a Therapeutic Strategy of Alzheimer’s Disease. InBiophysics and Biochemistry of Protein Aggregation: Experimental and Theoretical Studies on Folding, Misfolding, and Self-Assembly of Amyloidogenic Peptides (pp. 73-111).
  3. Lin, C. Y., Cheng, Y. S., Liao, T. Y., Lin, C., Chen, Z. T., Twu, W. I., … & Chen, R. P. Y. (2016). Intranasal administration of a polyethylenimine-conjugated scavenger peptide reduces amyloid-β accumulation in a mouse model of Alzheimer’s disease.Journal of Alzheimer’s Disease53(3), 1053-1067.
  4. Lo, W. L., Wang, Y. H., Chen, E. H., Wang, S. M., Chen, L. C., & Chen, R. P. (2022). Biodistribution analysis of an intranasal-delivered peptide by the nanoSPECT/CT imaging.Journal of Drug Delivery Science and Technology73, 103454.
  5. Qiu, T., Liu, Q., Chen, Y. X., Zhao, Y. F., & Li, Y. M. (2015). Aβ42 and Aβ40: similarities and differences.Journal of Peptide Science21(7), 522-529
  6. Rabiee, N., Ahmadi, S., Afshari, R., Khalaji, S., Rabiee, M., Bagherzadeh, M., … & Webster, T. J. (2021). Polymeric nanoparticles for nasal drug delivery to the brain: relevance to Alzheimer’s disease.Advanced Therapeutics4(3), 2000076.
  7. Ribarič, S. (2018). Peptides as potential therapeutics for Alzheimer’s disease.Molecules23(2), 283.



Figure 3. V24P(10–40)-PEI reduces amyloid-β plaque accumulation in APP/PS1 mice


Table 1: Comparison of V24P(10–40)-PEI with different peptides used in AD models

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