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Updated: Jul 31, 2025
Detecting Amyloid-β Accumulation via Immunofluorescent Staining in a Mouse Model of Alzheimer's Disease
Published on: April 19, 2021
Peptide aptamer targeting Aβ-PrP-Fyn axis reduces Alzheimer's disease pathologies in 5XFAD transgenic mouse model
Tahir Ali1,2, Antonia N Klein1,2, Alex Vu1,2
1Calgary Prion Research Unit, Department of Comparative Biology & Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4Z6, Canada.
Abstract:
Currently, no effective therapeutics exist for the treatment of incurable neurodegenerative diseases such as Alzheimer's disease (AD). The cellular prion protein (PrPC) acts as a high-affinity receptor for amyloid beta oligomers (AβO), a main neurotoxic species mediating AD pathology. The interaction of AβO with PrPC subsequently activates Fyn tyrosine kinase and neuroinflammation. Herein, we used our previously developed peptide aptamer 8 (PA8) binding to PrPC as a therapeutic to target the AβO-PrP-Fyn axis and prevent its associated pathologies. Our in vitro results indicated that PA8 prevents the binding of AβO with PrPC and reduces AβO-induced neurotoxicity in mouse neuroblastoma N2a cells and primary hippocampal neurons. Next, we performed in vivo experiments using the transgenic 5XFAD mouse model of AD. The 5XFAD mice were treated with PA8 and its scaffold protein thioredoxin A (Trx) at a 14.4 µg/day dosage for 12 weeks by intraventricular infusion through Alzet® osmotic pumps. We observed that treatment with PA8 improves learning and memory functions of 5XFAD mice as compared to Trx-treated 5XFAD mice. We found that PA8 treatment significantly reduces AβO levels and Aβ plaques in the brain tissue of 5XFAD mice. Interestingly, PA8 significantly reduces AβO-PrP interaction and its downstream signaling such as phosphorylation of Fyn kinase, reactive gliosis as well as apoptotic neurodegeneration in the 5XFAD mice compared to Trx-treated 5XFAD mice. Collectively, our results demonstrate that treatment with PA8 targeting the AβO-PrP-Fyn axis is a promising and novel approach to prevent and treat AD.
Insights
A novel peptide aptamer, PA8, effectively targets the amyloid beta oligomer-prion protein interaction, reducing neurotoxicity and improving cognitive function in Alzheimer's disease models.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Neurodegenerative diseases like Alzheimer's disease (AD) lack effective treatments.
- Amyloid beta oligomers (AβO) are key neurotoxic species in AD pathology.
- The cellular prion protein (PrPC) acts as a receptor for AβO, initiating downstream neuroinflammation and toxicity.
Purpose of the Study:
- To evaluate peptide aptamer 8 (PA8) as a therapeutic agent targeting the AβO-PrP-Fyn axis.
- To investigate PA8's efficacy in preventing AβO-induced neurotoxicity and AD-related pathologies.
Main Methods:
- In vitro studies using neuroblastoma cells and primary neurons to assess AβO binding to PrPC and neurotoxicity.
- In vivo experiments using 5XFAD transgenic mice treated with PA8 via intraventricular infusion for 12 weeks.
- Assessment of cognitive function, AβO levels, Aβ plaques, PrP interaction, Fyn kinase phosphorylation, gliosis, and neurodegeneration.
Main Results:
- PA8 inhibited AβO binding to PrPC and reduced AβO-induced neurotoxicity in vitro.
- PA8 treatment improved learning and memory in 5XFAD mice.
- PA8 significantly decreased AβO levels, Aβ plaques, AβO-PrP interaction, Fyn kinase phosphorylation, gliosis, and apoptotic neurodegeneration in vivo.
Conclusions:
- PA8 effectively targets the AβO-PrP-Fyn pathway, a critical mediator of Alzheimer's disease pathology.
- PA8 demonstrates therapeutic potential for preventing and treating Alzheimer's disease by mitigating key pathological hallmarks.
